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http://www.ncbi.nlm.nih.gov/pubmed/21696723
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1. Injury. 2012 Mar;43(3):259-65. doi: 10.1016/j.injury.2011.05.035. Epub 2011
Jun 21.
Chondrocytes or adult stem cells for cartilage repair: the indisputable role of
growth factors.
Freyria AM(1), Mallein-Gerin F.
Author information:
(1)Cartilage Biology and Engineering Group, IBCP, Université Lyon 1, Univ Lyon,
CNRS FRE 3310, IFR128, France. [email protected]
Articular cartilage is easily injured but difficult to repair and cell therapies
are proposed as tools to regenerate the defects in the tissue. Both
differentiated chondrocytes and adult mesenchymal stem cells (MSCs) are regarded
as cells potentially able to restore a functional cartilage. However, it is a
complex process from the cell level to the tissue end product, during which
growth factors play important roles from cell proliferation, extracellular
matrix synthesis, maintenance of the phenotype to induction of MSCs towards
chondrogenesis. Members of the TGF-β superfamily, are especially important in
fulfilling these roles. Depending on the cell type chosen to restore cartilage,
the effect of growth factors will vary. In this review, the roles of these
factors in the maintenance of the chondrocyte phenotype are discussed and
compared with those of factors involved in the repair of cartilage defects,
using chondrocytes or adult mesenchymal stem cells.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.injury.2011.05.035
PMID: 21696723 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23637149
|
1. J Am Acad Orthop Surg. 2013 May;21(5):303-11. doi: 10.5435/JAAOS-21-05-303.
Cartilage regeneration.
Tuan RS(1), Chen AF, Klatt BA.
Author information:
(1)Department of Orthopaedic Surgery, University of Pittsburgh, PA, USA.
Cartilage damaged by trauma has a limited capacity to regenerate. Current
methods of managing small chondral defects include palliative treatment with
arthroscopic débridement and lavage, reparative treatment with
marrow-stimulation techniques (eg, microfracture), and restorative treatment,
including osteochondral grafting and autologous chondrocyte implantation. Larger
defects are managed with osteochondral allograft or total joint arthroplasty.
However, the future of managing cartilage defects lies in providing biologic
solutions through cartilage regeneration. Laboratory and clinical studies have
examined the management of larger lesions using tissue-engineered cartilage.
Regenerated cartilage can be derived from various cell types, including
chondrocytes, pluripotent stem cells, and mesenchymal stem cells. Common
scaffolding materials include proteins, carbohydrates, synthetic materials, and
composite polymers. Scaffolds may be woven, spun into nanofibers, or configured
as hydrogels. Chondrogenesis may be enhanced with the application of
chondroinductive growth factors. Bioreactors are being developed to enhance
nutrient delivery and provide mechanical stimulation to tissue-engineered
cartilage ex vivo. The multidisciplinary approaches currently being developed to
produce cartilage promise to bring to fruition the desire for cartilage
regeneration in clinical use.
DOI: 10.5435/JAAOS-21-05-303
PMCID: PMC4886741
PMID: 23637149 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36196023
|
1. Br J Pharmacol. 2023 Jan;180(1):5-24. doi: 10.1111/bph.15968. Epub 2022 Oct
24.
RNA N(6) -methyladenosine modifications and potential targeted therapeutic
strategies in kidney disease.
Ni WJ(1)(2)(3), Lu H(2), Ma NN(4), Hou BB(5), Zeng J(3), Zhou H(6), Shao W(7),
Meng XM(2).
Author information:
(1)Department of Pharmacy, Anhui Provincial Hospital, The First Affiliated
Hospital of USTC, Division of Life Sciences and Medicine, University of Science
and Technology of China, Hefei, Anhui, 230001, China.
(2)Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui
Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University,
Hefei, Anhui, 230032, China.
(3)Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, 230001,
China.
(4)Department of Urology, The Second Affiliated Hospital of Anhui Medical
University, Hefei, Anhui, 230601, China.
(5)Department of Urology, The First Affiliated Hospital of Anhui Medical
University, Hefei, Anhui, 230022, China.
(6)Department of Pharmacy, Anhui Provincial Cancer Hospital, The First
Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University
of Science and Technology of China, Hefei, Anhui, 230031, China.
(7)School of Basic Medicine, Anhui Medical University, Hefei, Anhui, 230032,
China.
Epigenetic modifications have received increasing attention and have been shown
to be extensively involved in kidney development and disease progression. Among
them, the most common RNA modification, N6 -methyladenosine (m6 A), has been
shown to dynamically and reversibly exert its functions in multiple ways,
including splicing, export, decay and translation initiation efficiency to
regulate mRNA fate. Moreover, m6 A has also been reported to exert biological
effects by destabilizing base pairing to modulate various functions of RNAs.
Most importantly, an increasing number of kidney diseases, such as renal cell
carcinoma, acute kidney injury and chronic kidney disease, have been found to be
associated with aberrant m6 A patterns. In this review, we comprehensively
review the critical roles of m6 A in kidney diseases and discuss the
possibilities and relevance of m6 A-targeted epigenetic therapy, with an
integrated comprehensive description of the detailed alterations in specific
loci that contribute to cellular processes that are associated with kidney
diseases.
© 2022 British Pharmacological Society.
DOI: 10.1111/bph.15968
PMID: 36196023 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36314059
|
1. Exp Dermatol. 2023 Jan;32(1):4-12. doi: 10.1111/exd.14696. Epub 2022 Nov 13.
N6-methyladenosine functions and its role in skin cancer.
Ran Y(1), Yan Z(1), Jiang B(1)(2), Liang P(1).
Author information:
(1)Department of Burns and Plastic Surgery, Xiangya Hospital, Central South
University, Changsha, P. R. China.
(2)Department of Pathophysiology, Xiangya School of Medicine, Central South
University, Changsha, P. R. China.
N6-methyladenosine (m6A) methylation is the most abundant mammalian mRNA
modification. m6A regulates RNA processing, splicing, nucleation, translation
and stability by transferring, removing and recognizing m6A methylation sites,
which are critical for cancer initiation, progression, metabolism and
metastasis. m6A is involved in pathophysiological tumour development by altering
m6A modification and expression levels in tumour oncogenes and suppressor genes.
Skin cancers are by far the most common malignancies in humans, with well over a
million cases diagnosed each year. Skin cancers are grouped into two main
categories: melanoma and non-melanoma skin cancers (NMSC), based on cell origin
and clinical behaviour. In this review, we summarize m6A methylation functions
in different skin cancers, and discuss how m6A methylation is involved in
disease development and progression. Moreover, we review potential prognostic
biomarkers and molecular targets for early skin cancer diagnosis and treatment.
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/exd.14696
PMID: 36314059 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34130310
|
1. Pain. 2021 Jul 1;162(7):1960-1976. doi: 10.1097/j.pain.0000000000002218.
Methyltransferase-like 3 contributes to inflammatory pain by targeting TET1 in
YTHDF2-dependent manner.
Pan Z(1), Zhang Q(1), Liu X(1), Zhou H(1), Jin T(2), Hao LY(1), Xie L(1), Zhang
M(1), Yang XX(1), Sun ML(1), Xue ZY(1), Tao Y(1), Ye XC(3), Shen W(4), Cao
JL(1)(5).
Author information:
(1)Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key
Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical
University, Xuzhou, China.
(2)Department of Pain, Shanghai Tenth People's Hospital, Tongji University,
Shanghai, China.
(3)Department of Neurology, The Affiliated Hospital of Xuzhou Medical
University, Xuzhou, Jiangsu Province, China.
(4)Department of Pain, The Affiliated Hospital of Xuzhou Medical University,
Xuzhou, China.
(5)Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical
University, Xuzhou, China.
Comment in
Pain. 2021 Jul 1;162(7):1897-1898. doi: 10.1097/j.pain.0000000000002219.
The methyltransferase-like 3 (Mettl3) is a key component of the large
N6-adenosine-methyltransferase complex in mammalian responsible for RNA
N6-methyladenosine (m6A) modification, which plays an important role in gene
post-transcription modulation. Although RNA m6A is enriched in mammalian
neurons, its regulatory function in nociceptive information processing remains
elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced
inflammatory pain significantly decreased global m6A level and m6A writer Mettl3
in the spinal cord. Mimicking this decease by knocking down or conditionally
deleting spinal Mettl3 elevated the levels of m6A in ten-eleven translocation
methylcytosine dioxygenases 1 (Tet1) mRNA and TET1 protein in the spinal cord,
leading to production of pain hypersensitivity. By contrast, overexpressing
Mettl3 reversed a loss of m6A in Tet1 mRNA and blocked the CFA-induced increase
of TET1 in the spinal cord, resulting in the attenuation of pain behavior.
Furthermore, the decreased level of spinal YT521-B homology domain family
protein 2 (YTHDF2), an RNA m6A reader, stabilized upregulation of spinal TET1
because of the reduction of Tet1 mRNA decay by the binding to m6A in Tet1 mRNA
in the spinal cord after CFA. This study reveals a novel mechanism for
downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the
modulation of inflammatory pain through stabilizing upregulation of TET1 in
spinal neurons.
Copyright © 2021 International Association for the Study of Pain.
DOI: 10.1097/j.pain.0000000000002218
PMID: 34130310 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33630241
|
1. J Cardiovasc Transl Res. 2021 Oct;14(5):857-872. doi:
10.1007/s12265-021-10108-w. Epub 2021 Feb 25.
N6-Adenosine Methylation (m(6)A) RNA Modification: an Emerging Role in
Cardiovascular Diseases.
Chen YS(#)(1)(2), Ouyang XP(#)(3)(4), Yu XH(#)(5), Novák P(2), Zhou L(2), He
PP(6)(7), Yin K(8).
Author information:
(1)School of Nursing, University of South China, Hengyang, Hunan, 421001, China.
(2)Guangxi Key Laboratory of Diabetic Systems Medicine, The Second Affiliated
Hospital of Guilin Medical University, Guilin Medical University, Guilin,
541100, China.
(3)Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment,
Department of Physiology, The Neuroscience Institute, Hengyang Medical College,
University of South China, Hengyang, 421001, Hunan, China.
(4)Hunan Province Cooperative Innovation Center for Molecular Target New Drug
Study, University of South China, Hengyang, 421001, Hunan, China.
(5)Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan
Medical University, Haikou, 460106, Hainan, China.
(6)School of Nursing, University of South China, Hengyang, Hunan, 421001, China.
[email protected].
(7)Hunan Province Cooperative Innovation Center for Molecular Target New Drug
Study, University of South China, Hengyang, 421001, Hunan, China.
[email protected].
(8)Guangxi Key Laboratory of Diabetic Systems Medicine, The Second Affiliated
Hospital of Guilin Medical University, Guilin Medical University, Guilin,
541100, China. [email protected].
(#)Contributed equally
N6-methyladenosine (m6A) is the most abundant and prevalent epigenetic
modification of mRNA in mammals. This dynamic modification is regulated by m6A
methyltransferases and demethylases, which control the fate of target mRNAs
through influencing splicing, translation and decay. Recent studies suggest that
m6A modification plays an important role in the progress of cardiac remodeling
and cardiomyocyte contractile function. However, the exact roles of m6A in
cardiovascular diseases (CVDs) have not been fully explained. In this review, we
summarize the current roles of the m6A methylation in the progress of CVDs, such
as cardiac remodeling, heart failure, atherosclerosis (AS), and congenital heart
disease. Furthermore, we seek to explore the potential risk mechanisms of m6A in
CVDs, including obesity, inflammation, adipogenesis, insulin resistance (IR),
hypertension, and type 2 diabetes mellitus (T2DM), which may provide novel
therapeutic targets for the treatment of CVDs.
© 2021. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC part of Springer Nature.
DOI: 10.1007/s12265-021-10108-w
PMID: 33630241 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/31188932
|
1. Genet Mol Biol. 2019 Jul-Sep;42(3):666-670. doi:
10.1590/1678-4685-GMB-2018-0212. Epub 2019 Nov 14.
The perturbed expression of m6A in parthenogenetic mouse embryos.
Hao J(1), Xianfeng Y(1), Gao W(1), Wei J(1), Qi M(1), Han L(1), Shi S(1), Lin
C(2), Wang D(1).
Author information:
(1)Laboratory Animal Center, College of Animal Science, Jilin University,
Changchun, China.
(2)Department of Emergency, First Hospital, Jilin University, Changchun, Jilin,
China.
Parthenogenetically activated oocytes cannot develop to term in mammals owing to
abnormal epigenetic modifications. Methylation of the N6 position of adenosine
(m6A) is a post-transcriptional epigenetic modification of RNA. To investigate
the role of m6A methylation in parthenogenetic (PA) embryonic development, we
analyzed METTL3, METTL14, FTO, ALKBH5, YTHDF2, IGF2BP1, and IGF2BP2 expression
by quantitative real-time PCR. These genes were found dynamically expressed
during the 2-cell, 4-cell, 8-cell, and blastocyst stages of the embryo. Compared
to normally fertilized embryos, the expression of these genes was perturbed in
PA embryos, especially at the 8-cell stage. Furthermore, immunofluorescence was
used to detect m6A expression. The results demonstrated that m6A expression
decreased in the 2-cell stage, whereas it increased in the 8-cell stage of PA
embryos. Taken together, these results suggest that the expression of RNA
methylation-related genes was perturbed, leading to abnormal m6A modification
during early development in PA embryos.
DOI: 10.1590/1678-4685-GMB-2018-0212
PMCID: PMC6905444
PMID: 31188932
|
http://www.ncbi.nlm.nih.gov/pubmed/35748227
|
1. Mol Cells. 2022 Jul 31;45(7):435-443. doi: 10.14348/molcells.2022.0017. Epub
2022 Jun 24.
m(6)A in the Signal Transduction Network.
Jang KH(1), Heras CR(1)(2), Lee G(1).
Author information:
(1)Department of Microbiology and Molecular Genetics, Chao Family Comprehensive
Cancer Center, School of Medicine, University of California Irvine, Irvine, CA
92617, USA.
(2)School of Biological Sciences, University of California Irvine, Irvine, CA
92697, USA.
In response to environmental changes, signaling pathways rewire gene expression
programs through transcription factors. Epigenetic modification of the
transcribed RNA can be another layer of gene expression regulation. N6-adenosine
methylation (m6A) is one of the most common modifications on mRNA. It is a
reversible chemical mark catalyzed by the enzymes that deposit and remove methyl
groups. m6A recruits effector proteins that determine the fate of mRNAs through
changes in splicing, cellular localization, stability, and translation
efficiency. Emerging evidence shows that key signal transduction pathways
including TGFβ (transforming growth factor-β), ERK (extracellular
signal-regulated kinase), and mTORC1 (mechanistic target of rapamycin complex 1)
regulate downstream gene expression through m6A processing. Conversely, m6A can
modulate the activity of signal transduction networks via m6A modification of
signaling pathway genes or by acting as a ligand for receptors. In this review,
we discuss the current understanding of the crosstalk between m6A and signaling
pathways and its implication for biological systems.
DOI: 10.14348/molcells.2022.0017
PMCID: PMC9260138
PMID: 35748227 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST The authors have no
potential conflicts of interest to disclose.
|
http://www.ncbi.nlm.nih.gov/pubmed/29082271
|
1. Inflamm Cell Signal. 2017;4(3):e1604. Epub 2017 Oct 17.
RNA N(6)-adenosine methylation (m(6)A) steers epitranscriptomic control of
herpesvirus replication.
Ye F(1).
Author information:
(1)Department of Microbiology and Molecular Biology, School of Medicine, Case
Western Reserve University, 10900 Euclid avenue, Cleveland, 44106 Ohio, USA.
Latency is a hallmark of all herpesviruses, during which the viral genomes are
silenced through DNA methylation and suppressive histone modifications. When
latent herpesviruses reactivate to undergo productive lytic replication, the
suppressive epigenetic marks are replaced with active ones to allow for
transcription of viral genes. Interestingly, by using Kaposi's
sarcoma-associated herpesvirus (KSHV) as a model, we recently demonstrated that
the newly transcribed viral RNAs are also subjected to post-transcriptional
N6-adenosine methylation (m6A). Blockade of this post-transcriptional event
abolishes viral protein expression and halts virion production. We found that
m6A modification controls RNA splicing, stability, and protein translation to
regulate viral lytic gene expression and replication. Thus, our finding for the
first time reveals a critical role of this epitranscriptomic mechanism in the
control of herpesviral replication, which shall shed lights on development of
novel strategies for the control of herpesviral infection.
PMCID: PMC5659614
PMID: 29082271
Conflict of interest statement: Conflicting interests The authors have declared
that no conflict of interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/33999093
|
1. Genet Mol Biol. 2021 May 14;44(2):e20200253. doi:
10.1590/1678-4685-GMB-2020-0253. eCollection 2021.
Role of N6-methyl-adenosine modification in mammalian embryonic development.
Li C(1), Jiang Z(2), Hao J(1), Liu D(3), Hu H(1), Gao Y(1), Wang D(1).
Author information:
(1)Jilin University, College of Animal Science, Laboratory Animal Center,
Changchun, China.
(2)The First Hospital of Jilin University, Department of hand surgery,
Changchun, China.
(3)Changchun University of Chinese Medicine, Department of Pharmacy, Changchun,
China.
N6-methyl-adenosine (m6A) methylation is one of the most common and abundant
modifications of RNA molecules in eukaryotes. Although various biological roles
of m6A methylation have been elucidated, its role in embryonic development is
still unclear. In this review, we focused on the function and expression
patterns of m6A-related genes in mammalian embryonic development and the role of
m6A modification in the embryonic epigenetic reprogramming process. The
modification of m6A is regulated by the combined activities of
methyltransferases, demethylases, and m6A-binding proteins. m6A-related genes
act synergistically to form a dynamic, reversible m6A pattern, which exists in
several physiological processes in various stages of embryonic development. The
lack of one of these enzymes affects embryonic m6A levels, leading to abnormal
embryonic development and even death. Moreover, m6A is a positive regulator of
reprogramming to pluripotency and can affect embryo reprogramming by affecting
activation of the maternal-to-zygotic transition. In conclusion, m6A is involved
in the regulation of gene expression during embryonic development and the
metabolic processes of RNA and plays an important role in the epigenetic
modification of embryos.
DOI: 10.1590/1678-4685-GMB-2020-0253
PMCID: PMC8127566
PMID: 33999093
Conflict of interest statement: Conflict of Interest: The authors declare that
they have no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/33839323
|
1. Mol Ther. 2021 May 5;29(5):1703-1715. doi: 10.1016/j.ymthe.2021.04.009. Epub
2021 Apr 9.
The evolving landscape of N(6)-methyladenosine modification in the tumor
microenvironment.
Gu Y(1), Wu X(1), Zhang J(2), Fang Y(1), Pan Y(1), Shu Y(3), Ma P(4).
Author information:
(1)Department of Oncology, the First Affiliated Hospital of Nanjing Medical
University, Nanjing 210029, People's Republic of China.
(2)Department of General Surgery, The Affiliated People's Hospital of Jiangsu
University, Zhenjiang Clinic School of Nanjing Medical University, Zhenjiang
212002, People's Republic of China.
(3)Department of Oncology, the First Affiliated Hospital of Nanjing Medical
University, Nanjing 210029, People's Republic of China; Jiangsu Key Lab of
Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for
Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166,
People's Republic of China. Electronic address: [email protected].
(4)Department of Oncology, the First Affiliated Hospital of Nanjing Medical
University, Nanjing 210029, People's Republic of China. Electronic address:
[email protected].
The tumor microenvironment (TME), controlled by intrinsic mechanisms of
carcinogenesis and epigenetic modifications, has, in recent years, become a
heavily researched topic. The TME can be described in terms of hypoxia,
metabolic dysregulation, immune escape, and chronic inflammation. RNA
methylation, an epigenetic modification, has recently been found to have a
pivotal role in shaping the TME. The N6-methylation of adenosine (m6A)
modification is the most common type of RNA methylation that occurs in the
N6-position of adenosine, which is the primary internal modification of
eukaryotic mRNA. Compelling evidence has demonstrated that m6A regulates
transcriptional and protein expression through splicing, translation,
degradation, and export, thereby mediating the biological processes of cancer
cells and/or stromal cells and characterizing the TME. The TME also has a
crucial role in the complicated regulatory network of m6A modifications and,
subsequently, influences tumor initiation, progression, and therapy responses.
In this review, we describe the features of the TME and how the m6A modification
modulates and interacts with it. We also focus on various factors and pathways
involved in m6A methylation. Finally, we discuss potential therapeutic
strategies and prognostic biomarkers with respect to the TME and m6A
modification.
Copyright © 2021 The American Society of Gene and Cell Therapy. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymthe.2021.04.009
PMCID: PMC8116604
PMID: 33839323 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors declare no
competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/23453015
|
1. Genomics Proteomics Bioinformatics. 2013 Feb;11(1):8-17. doi:
10.1016/j.gpb.2012.12.002. Epub 2012 Dec 21.
N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic
function.
Niu Y(1), Zhao X, Wu YS, Li MM, Wang XJ, Yang YG.
Author information:
(1)Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of
Genomics, Chinese Academy of Sciences, Beijing 100101, China.
N(6)-methyl-adenosine (m(6)A) is one of the most common and abundant
modifications on RNA molecules present in eukaryotes. However, the biological
significance of m(6)A methylation remains largely unknown. Several independent
lines of evidence suggest that the dynamic regulation of m(6)A may have a
profound impact on gene expression regulation. The m(6)A modification is
catalyzed by an unidentified methyltransferase complex containing at least one
subunit methyltransferase like 3 (METTL3). m(6)A modification on messenger RNAs
(mRNAs) mainly occurs in the exonic regions and 3'-untranslated region (3'-UTR)
as revealed by high-throughput m(6)A-seq. One significant advance in m(6)A
research is the recent discovery of the first two m(6)A RNA demethylases fat
mass and obesity-associated (FTO) gene and ALKBH5, which catalyze m(6)A
demethylation in an α-ketoglutarate (α-KG)- and Fe(2+)-dependent manner. Recent
studies in model organisms demonstrate that METTL3, FTO and ALKBH5 play
important roles in many biological processes, ranging from development and
metabolism to fertility. Moreover, perturbation of activities of these enzymes
leads to the disturbed expression of thousands of genes at the cellular level,
implicating a regulatory role of m(6)A in RNA metabolism. Given the vital roles
of DNA and histone methylations in epigenetic regulation of basic life processes
in mammals, the dynamic and reversible chemical m(6)A modification on RNA may
also serve as a novel epigenetic marker of profound biological significances.
Copyright © 2013. Production and hosting by Elsevier Ltd.
DOI: 10.1016/j.gpb.2012.12.002
PMCID: PMC4357660
PMID: 23453015 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35095893
|
1. Front Immunol. 2022 Jan 12;12:806189. doi: 10.3389/fimmu.2021.806189.
eCollection 2021.
N6-Methyladenosine-Related LncRNAs Are Potential Remodeling Indicators in the
Tumor Microenvironment and Prognostic Markers in Osteosarcoma.
Wu Z(1), Zhang X(2), Chen D(3), Li Z(4), Wu X(2), Wang J(2), Deng Y(2).
Author information:
(1)Department of Laboratory Medicine, The Third Xiangya Hospital, Central South
University, Changsha, China.
(2)Department of Spine Surgery, Third Xiangya Hospital, Central South
University, Changsha, China.
(3)Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital,
Central South University, Changsha, China.
(4)Department of Clinical Laboratory, Qinghai Provincial People's Hospital,
Xining, China.
N6-Adenosine methylation, yielding N6-methyladenosine (m6A), is a reversible
epigenetic modification found in messenger RNAs and long non-coding RNAs
(lncRNAs), which affects the fate of modified RNA molecules and is essential for
the development and differentiation of immune cells in the tumor
microenvironment (TME). Osteosarcoma (OS) is the most common primary bone tumor
in children and adolescents, and is characterized by high mortality. Currently,
the possible role of m6A modifications in the prognosis of OS is unclear. In the
present study, we investigated the correlation between m6A-related lncRNA
expression and the clinical outcomes of OS patients via a comprehensive
analysis. Clinical and workflow-type data were obtained from the Genotype-Tissue
Expression Program and The Cancer Genome Atlas. We examined the relationship
between m6A modifications and lncRNA expression, conducted Kyoto Encyclopedia of
Genes analysis and also gene set enrichment analysis (GSEA), implemented
survival analysis to investigate the association of clinical survival data with
the expression of m6A-related lncRNAs, and utilized Lasso regression to model
the prognosis of OS. Furthermore, we performed immune correlation analysis and
TME differential analysis to investigate the infiltration levels of immune cells
and their relationship with clinical prognosis. LncRNA expression and m6A levels
were closely associated in co-expression analysis. The expression of m6A-related
lncRNAs was quite low in tumor tissues; this appeared to be a predicting factor
of OS in a prognostic model, independent of other clinical features. The
NOD-like receptor signaling pathway was the most significantly enriched pathway
in GSEA. In tumor tissues, SPAG4 was overexpressed while ZBTB32 and DEPTOR were
downregulated. Tissues in cluster 2 were highly infiltrated by plasma cells.
Cluster 2 presented higher ESTIMATE scores and stromal scores, showing a lower
tumor cell purity in the TME. In conclusion, m6A-related lncRNA expression is
strongly associated with the occurrence and development of OS, and can be used
to as a prognostic factor of OS. Moreover, m6A-related lncRNAs and infiltrating
immune cells in the TME could serve as new therapeutic targets and prognostic
biomarkers for OS.
Copyright © 2022 Wu, Zhang, Chen, Li, Wu, Wang and Deng.
DOI: 10.3389/fimmu.2021.806189
PMCID: PMC8790065
PMID: 35095893 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/29036602
|
1. Nucleic Acids Res. 2017 Nov 16;45(20):11594-11606. doi: 10.1093/nar/gkx883.
N6-adenine DNA methylation is associated with the linker DNA of H2A.Z-containing
well-positioned nucleosomes in Pol II-transcribed genes in Tetrahymena.
Wang Y(1), Chen X(1), Sheng Y(1), Liu Y(2), Gao S(1)(3).
Author information:
(1)Institute of Evolution & Marine Biodiversity, Ocean University of China,
Qingdao 266003, China.
(2)Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
(3)Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory
for Marine Science and Technology, Qingdao 266003, China.
DNA N6-methyladenine (6mA) is newly rediscovered as a potential epigenetic mark
across a more diverse range of eukaryotes than previously realized. As a
unicellular model organism, Tetrahymena thermophila is among the first
eukaryotes reported to contain 6mA modification. However, lack of comprehensive
information about 6mA distribution hinders further investigations into its
function and regulatory mechanism. In this study, we provide the first
genome-wide, base pair-resolution map of 6mA in Tetrahymena by applying
single-molecule real-time (SMRT) sequencing. We provide evidence that 6mA occurs
mostly in the AT motif of the linker DNA regions. More strikingly, these linker
DNA regions with 6mA are usually flanked by well-positioned nucleosomes and/or
H2A.Z-containing nucleosomes. We also find that 6mA is exclusively associated
with RNA polymerase II (Pol II)-transcribed genes, but is not an unambiguous
mark for active transcription. These results support that 6mA is an integral
part of the chromatin landscape shaped by adenosine triphosphate (ATP)-dependent
chromatin remodeling and transcription.
© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkx883
PMCID: PMC5714169
PMID: 29036602 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35032318
|
1. Mol Neurobiol. 2022 Mar;59(3):1925-1937. doi: 10.1007/s12035-022-02739-0. Epub
2022 Jan 15.
N6-methyladenosine and Neurological Diseases.
Zhang N(#)(1), Ding C(#)(1), Zuo Y(1), Peng Y(1), Zuo L(2).
Author information:
(1)Department of Physiology, Institute of Neuroscience Research, Hengyang Key
Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical
College, University of South China, 28 West Changsheng Road, Hengyang, 421001,
Hunan, China.
(2)Department of Physiology, Institute of Neuroscience Research, Hengyang Key
Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical
College, University of South China, 28 West Changsheng Road, Hengyang, 421001,
Hunan, China. [email protected].
(#)Contributed equally
N6-methyladenosine (m6A) is a dynamic reversible methylation modification of the
adenosine N6 position and is the most common chemical epigenetic modification
among mRNA post-transcriptional modifications, including methylation,
demethylation, and recognition. Post-transcriptional modification involves
multiple protein molecules, including METTL3, METTL14, WTAP, KIAA1429, ALKBH5,
YTHDF1/2/3, and YTHDC1/2. m6A-related proteins are expressed in almost all
cells. However, the abnormal expression of m6A-related proteins may occur in the
nervous system, thereby affecting neuritogenesis, brain volume, learning and
memory, memory formation and consolidation, etc., and is implicated in the
development of diseases, such as Parkinson's disease, Alzheimer's disease,
multiple sclerosis, depression, epilepsy, and brain tumors. This review focuses
on the functions of m6A in the development of central nervous system diseases,
thus contributing to a deeper understanding of disease pathogenesis and
providing potential clinical therapeutic targets for neurological diseases.
© 2022. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s12035-022-02739-0
PMID: 35032318 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35696004
|
1. Planta. 2022 Jun 13;256(1):9. doi: 10.1007/s00425-022-03926-y.
Same modification, different location: the mythical role of N(6)-adenine
methylation in plant genomes.
Jiménez-Ramírez IA(#)(1), Pijeira-Fernández G(#)(1), Moreno-Cálix DM(1),
De-la-Peña C(2).
Author information:
(1)Unidad de Bioquímica y Biología Molecular de Plantas, Centro de Investigación
Científica de Yucatán, Calle 43 No. 130 x 32 y 34. Col. Chuburná de Hidalgo,
97205, Mérida, Yucatán, Mexico.
(2)Centro de Investigación Científica de Yucatán, Unidad de Biotecnología, Calle
43 No. 130 x 32 y 34. Col. Chuburná de Hidalgo, 97205, Mérida, Yucatán, Mexico.
[email protected].
(#)Contributed equally
The present review summarizes recent advances in the understanding of 6mA in DNA
as an emergent epigenetic mark with distinctive characteristics, discusses its
importance in plant genomes, and highlights its chemical nature and functions.
Adenine methylation is an epigenetic modification present in DNA (6mA) and RNA
(m6A) that has a regulatory function in many cellular processes. This
modification occurs through a reversible reaction that covalently binds a methyl
group, usually at the N6 position of the purine ring. This modification carries
biophysical properties that affect the stability of nucleic acids as well as
their binding affinity with other molecules. DNA 6mA has been related to genome
stability, gene expression, DNA replication, and repair mechanisms. Recent
advances have shown that 6mA in plant genomes is related to development and
stress response. In this review, we present recent advances in the understanding
of 6mA in DNA as an emergent epigenetic mark with distinctive characteristics.
We discuss the key elements of this modification, focusing mainly on its
importance in plant genomes. Furthermore, we highlight its chemical nature and
the regulatory effects that it exerts on gene expression and plant development.
Finally, we emphasize the functions of 6mA in photosynthesis, stress, and
flowering.
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany,
part of Springer Nature.
DOI: 10.1007/s00425-022-03926-y
PMID: 35696004 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32867812
|
1. Epigenetics Chromatin. 2020 Aug 31;13(1):33. doi: 10.1186/s13072-020-00355-7.
N(6)-Adenosine methylation on mRNA is recognized by YTH2 domain protein of human
malaria parasite Plasmodium falciparum.
Govindaraju G(1)(2), Kadumuri RV(3), Sethumadhavan DV(1)(2), Jabeena CA(1)(2),
Chavali S(3), Rajavelu A(4).
Author information:
(1)Pathogen Biology, Rajiv Gandhi Centre for Biotechnology (RGCB), Thycaud PO,
Thiruvananthapuram, Kerala, 695014, India.
(2)Manipal Academy of Higher Education, Tiger Circle Road, Madhav Nagar,
Manipal, Karnataka, 576104, India.
(3)Department of Biology, Indian Institute of Science Education and Research
(IISER) Tirupati, Karakambadi Road, Tirupati, Andhra Pradesh, 517507, India.
(4)Pathogen Biology, Rajiv Gandhi Centre for Biotechnology (RGCB), Thycaud PO,
Thiruvananthapuram, Kerala, 695014, India. [email protected].
Erratum in
Epigenetics Chromatin. 2020 Sep 22;13(1):36. doi:
10.1186/s13072-020-00357-5.
BACKGROUND: Plasmodium falciparum exhibits high translational plasticity during
its development in RBCs, yet the regulation at the post-transcriptional level is
not well understood. The N6-methyl adenosine (m6A) is an important epigenetic
modification primarily present on mRNA that controls the levels of transcripts
and efficiency of translation in eukaryotes. Recently, the dynamics of m6A on
mRNAs at all three developmental stages of P. falciparum in RBCs have been
profiled; however, the proteins that regulate the m6A containing mRNAs in the
parasites are unknown.
RESULTS: Using sequence analysis, we computationally identified that the P.
falciparum genome encodes two putative YTH (YT521-B Homology) domain-containing
proteins, which could potentially bind to m6A containing mRNA. We developed a
modified methylated RNA immunoprecipitation (MeRIP) assay using PfYTH2 and find
that it binds selectively to m6A containing transcripts. The PfYTH2 has a
conserved aromatic amino acid cage that forms the methyl-binding pocket. Through
site-directed mutagenesis experiments and molecular dynamics simulations, we
show that F98 residue is important for m6A binding on mRNA. Fluorescence
depolarization assay confirmed that PfYTH2 binds to methylated RNA oligos with
high affinity. Further, MeRIP sequencing data revealed that PfYTH2 has more
permissive sequence specificity on target m6A containing mRNA than other known
eukaryotic YTH proteins. Taken together, here we identify and characterize
PfYTH2 as the major protein that could regulate m6A containing transcripts in P.
falciparum.
CONCLUSION: Plasmodium spp. lost the canonical m6A-specific demethylases in
their genomes, however, the YTH domain-containing proteins seem to be retained.
This study presents a possibility that the YTH proteins are involved in
post-transcriptional control in P. falciparum, and might orchestrate the
translation of mRNA in various developmental stages of P. falciparum. This is
perhaps the first characterization of the methyl-reading function of YTH protein
in any parasites.
DOI: 10.1186/s13072-020-00355-7
PMCID: PMC7457798
PMID: 32867812 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/31801551
|
1. Mol Cancer. 2019 Dec 4;18(1):176. doi: 10.1186/s12943-019-1109-9.
Functions of N6-methyladenosine and its role in cancer.
He L(1)(2), Li H(1)(2), Wu A(1), Peng Y(1), Shu G(2), Yin G(3).
Author information:
(1)Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences,
Central South University, Changsha, 410008, Hunan Province, China.
(2)School of Basic Medical Sciences, Central South University, Changsha, 410013,
Hunan Province, China.
(3)Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences,
Central South University, Changsha, 410008, Hunan Province, China.
[email protected].
N6-methyladenosine (m6A) is methylation that occurs in the N6-position of
adenosine, which is the most prevalent internal modification on eukaryotic mRNA.
Accumulating evidence suggests that m6A modulates gene expression, thereby
regulating cellular processes ranging from cell self-renewal, differentiation,
invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by
m6A demethylases and recognized by reader proteins, which regulate of RNA
metabolism including translation, splicing, export, degradation and microRNA
processing. Alteration of m6A levels participates in cancer pathogenesis and
development via regulating expression of tumor-related genes like BRD4, MYC,
SOCS2 and EGFR. In this review, we elaborate on recent advances in research of
m6A enzymes. We also highlight the underlying mechanism of m6A in cancer
pathogenesis and progression. Finally, we review corresponding potential targets
in cancer therapy.
DOI: 10.1186/s12943-019-1109-9
PMCID: PMC6892141
PMID: 31801551 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they do not have any
conflicts of interest related to this study. This manuscript has been read and
approved by all the authors and has not been submitted to or is not under
consider for publication elsewhere.
|
http://www.ncbi.nlm.nih.gov/pubmed/34850126
|
1. Nucleic Acids Res. 2021 Dec 2;49(21):12048-12068. doi: 10.1093/nar/gkab1124.
Enzymatic deamination of the epigenetic nucleoside N6-methyladenosine regulates
gene expression.
Jiang Z(1), Wang C(1), Wu Z(1), Chen K(1), Yang W(1), Deng H(1), Song H(1), Zhou
X(1).
Author information:
(1)The Institute of Advanced Studies, and Key Laboratory of Biomedical
Polymers-Ministry of Education, College of Chemistry and Molecular Sciences,
Wuhan University, 40072 Wuhan, P.R. China.
N6-methyladenosine (m6A) modification is the most extensively studied epigenetic
modification due to its crucial role in regulating an array of biological
processes. Herein, Bsu06560, formerly annotated as an adenine deaminase derived
from Bacillus subtilis 168, was recognized as the first enzyme capable of
metabolizing the epigenetic nucleoside N6-methyladenosine. A model of Bsu06560
was constructed, and several critical residues were putatively identified via
mutational screening. Two mutants, F91L and Q150W, provided a superiorly
enhanced conversion ratio of adenosine and N6-methyladenosine. The CRISPR-Cas9
system generated Bsu06560-knockout, F91L, and Q150W mutations from the B.
subtilis 168 genome. Transcriptional profiling revealed a higher global gene
expression level in BS-F91L and BS-Q150W strains with enhanced
N6-methyladenosine deaminase activity. The differentially expressed genes were
categorized using GO, COG, KEGG and verified through RT-qPCR. This study
assessed the crucial roles of Bsu06560 in regulating adenosine and
N6-methyladenosine metabolism, which influence a myriad of biological processes.
This is the first systematic research to identify and functionally annotate an
enzyme capable of metabolizing N6-methyladenosine and highlight its significant
roles in regulation of bacterial metabolism. Besides, this study provides a
novel method for controlling gene expression through the mutations of critical
residues.
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkab1124
PMCID: PMC8643624
PMID: 34850126 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36407103
|
1. Front Cell Dev Biol. 2022 Nov 3;10:1055808. doi: 10.3389/fcell.2022.1055808.
eCollection 2022.
N (6)-methyladenosine RNA methylation: From regulatory mechanisms to potential
clinical applications.
Li P(1)(2), Wang Y(1), Sun Y(2), Jiang S(2), Li J(1).
Author information:
(1)Department of Oncology, Weifang Medical University, Weifang, China.
(2)BGI Genomics, BGI-Shenzhen, Shenzhen, China.
Epitranscriptomics has emerged as another level of epigenetic regulation similar
to DNA and histone modifications. N 6-methyladenosine (m6A) is one of the most
prevalent and abundant posttranscriptional modifications, widely distributed in
many biological species. The level of N 6-methyladenosine RNA methylation is
dynamically and reversibly regulated by distinct effectors including
methyltransferases, demethylases, histone modification and metabolites. In
addition, N 6-methyladenosine RNA methylation is involved in multiple RNA
metabolism pathways, such as splicing, localization, translation efficiency,
stability and degradation, ultimately affecting various pathological processes,
especially the oncogenic and tumor-suppressing activities. Recent studies also
reveal that N 6-methyladenosine modification exerts the function in immune cells
and tumor immunity. In this review, we mainly focus on the regulatory mechanisms
of N 6-methyladenosine RNA methylation, the techniques for detecting N
6-methyladenosine methylation, the role of N 6-methyladenosine modification in
cancer and other diseases, and the potential clinical applications.
Copyright © 2022 Li, Wang, Sun, Jiang and Li.
DOI: 10.3389/fcell.2022.1055808
PMCID: PMC9669580
PMID: 36407103
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/34039354
|
1. J Biomed Sci. 2021 May 27;28(1):40. doi: 10.1186/s12929-021-00734-6.
The m(6)A epitranscriptome on neural development and degeneration.
Yen YP(1), Chen JA(2).
Author information:
(1)Institute of Molecular Biology, Academia Sinica, Taipei, 11529, Taiwan.
[email protected].
(2)Institute of Molecular Biology, Academia Sinica, Taipei, 11529, Taiwan.
[email protected].
N6-methyladenosine (m6A) is the most prevalent, conserved, and abundant RNA
modification of the mRNAs of most eukaryotes, including mammals. Similar to
epigenetic DNA modifications, m6A has been proposed to function as a critical
regulator for gene expression. This modification is installed by m6A methylation
"writers" (Mettl3/Mettl14 methyltransferase complex), and it can be reversed by
demethylase "erasers" (Fto and Alkbh5). Furthermore, m6A can be recognized by
"readers" (Ythdf and Ythdc families), which may be interpreted to affect mRNA
splicing, stability, translation or localization. Levels of m6A methylation
appear to be highest in the brain, where it plays important functions during
embryonic stem cell differentiation, brain development, and neurodevelopmental
disorders. Depletion of the m6A methylation writer Mettl14 from mouse embryonic
nervous systems prolongs cell cycle progression of radial glia and extends
cortical neurogenesis into postnatal stages. Recent studies further imply that
dysregulated m6A methylation may be significantly correlated with
neurodegenerative diseases. In this review, we give an overview of m6A
modifications during neural development and associated disorders, and provide
perspectives for studying m6A methylation.
DOI: 10.1186/s12929-021-00734-6
PMCID: PMC8157406
PMID: 34039354 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/32245489
|
1. Mol Cancer. 2020 Apr 3;19(1):72. doi: 10.1186/s12943-020-01190-w.
m(6)A-dependent glycolysis enhances colorectal cancer progression.
Shen C(1), Xuan B(1), Yan T(1), Ma Y(1), Xu P(1), Tian X(1), Zhang X(1), Cao
Y(1), Ma D(1), Zhu X(1), Zhang Y(2), Fang JY(3), Chen H(4), Hong J(5).
Author information:
(1)State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of
Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology
and Hepatology; Shanghai Cancer Institute; Shanghai Institute of Digestive
Disease; Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145
Middle Shandong Road, Shanghai, 200001, China.
(2)Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical
University, Xuzhou, 221009, China.
(3)State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of
Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology
and Hepatology; Shanghai Cancer Institute; Shanghai Institute of Digestive
Disease; Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145
Middle Shandong Road, Shanghai, 200001, China. [email protected].
(4)State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of
Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology
and Hepatology; Shanghai Cancer Institute; Shanghai Institute of Digestive
Disease; Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145
Middle Shandong Road, Shanghai, 200001, China. [email protected].
(5)State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of
Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology
and Hepatology; Shanghai Cancer Institute; Shanghai Institute of Digestive
Disease; Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145
Middle Shandong Road, Shanghai, 200001, China. [email protected].
BACKGROUND: Epigenetic alterations are involved in various aspects of colorectal
carcinogenesis. N6-methyladenosine (m6A) modifications of RNAs are emerging as a
new layer of epigenetic regulation. As the most abundant chemical modification
of eukaryotic mRNA, m6A is essential for the regulation of mRNA stability,
splicing, and translation. Alterations of m6A regulatory genes play important
roles in the pathogenesis of a variety of human diseases. However, whether this
mRNA modification participates in the glucose metabolism of colorectal cancer
(CRC) remains uncharacterized.
METHODS: Transcriptome-sequencing and liquid chromatography-tandem mass
spectrometry (LC-MS) were performed to evaluate the correlation between m6A
modifications and glucose metabolism in CRC. Mass spectrometric metabolomics
analysis, in vitro and in vivo experiments were conducted to investigate the
effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing,
immunoprecipitation and RNA stability assay were used to explore the molecular
mechanism of METTL3 in CRC.
RESULTS: A strong correlation between METTL3 and 18F-FDG uptake was observed in
CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis
depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3
directly interacted with the 5'/3'UTR regions of HK2, and the 3'UTR region of
SLC2A1 (GLUT1), then further stabilized these two genes and activated the
glycolysis pathway. M6A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on
the m6A reader IGF2BP2 or IGF2BP2/3, respectively.
CONCLUSIONS: METTL3 is a functional and clinical oncogene in CRC. METTL3
stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m6A-IGF2BP2/3-
dependent mechanism. Targeting METTL3 and its pathway offer alternative rational
therapeutic targets in CRC patients with high glucose metabolism.
DOI: 10.1186/s12943-020-01190-w
PMCID: PMC7118901
PMID: 32245489 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/35752056
|
1. Acta Histochem. 2022 Aug;124(6):151916. doi: 10.1016/j.acthis.2022.151916.
Epub 2022 Jun 22.
METTL3 plays a crucial function in multiple biological processes.
Li G(1), Sun Z(1), Deng W(1), Cheng S(1), Liu X(1), Liu J(1), Tang X(1), Zhang
Z(2).
Author information:
(1)Department of Preventive Medicine, School of Public Health, Hengyang Medical
School, University of South China, Hengyang, China; Hunan Province Key
Laboratory of Typical Environmental Pollution and Health Hazardsa, Hengyang
Medical School, University of South China, Hengyang, China.
(2)Department of Preventive Medicine, School of Public Health, Hengyang Medical
School, University of South China, Hengyang, China; Hunan Province Key
Laboratory of Typical Environmental Pollution and Health Hazardsa, Hengyang
Medical School, University of South China, Hengyang, China. Electronic address:
[email protected].
The N6-methyladenosine (m6A) refers to the methylation of the N6 position of
adenosine of RNA adenine. The modification of m6A is one of the most abundant
epigenetic modifications in eukaryotic mRNA and non-coding RNA and is controlled
by methyltransferases and demethylases. The biological mechanism and
significance of m6A have been discovered with the development of m6A sequencing.
Various m6A complex components regulate the function of m6A on mRNA.
Methyltransferase-like 3 (METTL3) is one of the earliest identified m6A
methyltransferases which regulate the functions of m6A. A large number of
studies have shown that METTL3 establishes a cross-talk with tumor cells and
development of various human diseases. In this review, we will briefly elaborate
on the role of METTL3 in biological function, epithelial-mesenchymal transition
(EMT), inflammatory response and sensitivity to the resistance of chemo
radiotherapies. The underlying molecular mechanism demonstrated by METTL3 may
provide a possible target for treating and diagnosing human diseases.
Copyright © 2022 Elsevier GmbH. All rights reserved.
DOI: 10.1016/j.acthis.2022.151916
PMID: 35752056 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32513173
|
1. Mol Cancer. 2020 Jun 8;19(1):104. doi: 10.1186/s12943-020-01216-3.
Mechanism of RNA modification N6-methyladenosine in human cancer.
Zhou Z(1), Lv J(1), Yu H(1), Han J(1), Yang X(1), Feng D(1), Wu Q(1), Yuan B(1),
Lu Q(2), Yang H(3).
Author information:
(1)Department of Urology, The First Affiliated Hospital of Nanjing Medical
University, Nanjing, 210029, PR China.
(2)Department of Urology, The First Affiliated Hospital of Nanjing Medical
University, Nanjing, 210029, PR China. [email protected].
(3)Department of Urology, The First Affiliated Hospital of Nanjing Medical
University, Nanjing, 210029, PR China. [email protected].
Since the breakthrough discoveries of DNA and histone modifications, the field
of RNA modifications has gained increasing interest in the scientific community.
The discovery of N6-methyladenosine (m6A), a predominantly internal epigenetic
modification in eukaryotes mRNA, heralded the creation of the field of
epi-transcriptomics. This post-transcriptional RNA modification is dynamic and
reversible, and is regulated by methylases, demethylases and proteins that
preferentially recognize m6A modifications. Altered m6A levels affect RNA
processing, degradation and translation, thereby disrupting gene expression and
key cellular processes, ultimately resulting in tumor initiation and
progression. Furthermore, inhibitors and regulators of m6A-related factors have
been explored as therapeutic approaches for treating cancer. In the present
review, the mechanisms of m6A RNA modification, the clinicopathological
relevance of m6A alterations, the type and frequency of alterations and the
multiple functions it regulates in different types of cancer are discussed.
DOI: 10.1186/s12943-020-01216-3
PMCID: PMC7278081
PMID: 32513173 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/35406663
|
1. Cells. 2022 Mar 24;11(7):1101. doi: 10.3390/cells11071101.
Emerging Roles and Mechanism of m6A Methylation in Cardiometabolic Diseases.
Xu Z(1), Lv B(1), Qin Y(1), Zhang B(1).
Author information:
(1)Division of Sports Science and Physical Education, Tsinghua University,
Beijing 100084, China.
Cardiometabolic diseases (CMDs) are currently the leading cause of death and
disability worldwide, and their underlying regulatory mechanisms remain largely
unknown. N6-methyladenosine (m6A) methylation, the most common and abundant
epigenetic modification of eukaryotic mRNA, is regulated by m6A
methyltransferase, demethylase, and the m6A binding protein, which affect the
transcription, cleavage, translation, and degradation of target mRNA. m6A
methylation plays a vital role in the physiological and pathological processes
of CMDs. In this review, we summarize the role played by m6A methylation in
CMDs, including obesity, hypertension, pulmonary hypertension, ischemic heart
disease, myocardial hypertrophy, heart failure, and atherosclerosis. We also
describe mechanisms that potentially involve the participation of m6A
methylation, such as those driving calcium homeostasis, circadian rhythm, lipid
metabolism, autophagy, macrophage response, and inflammation. m6A methylation
and its regulators are expected to be targets for the treatment of CMDs.
DOI: 10.3390/cells11071101
PMCID: PMC8997388
PMID: 35406663 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/31243897
|
1. Cancer Med. 2019 Aug;8(10):4766-4781. doi: 10.1002/cam4.2360. Epub 2019 Jun
26.
Reduced m6A modification predicts malignant phenotypes and augmented
Wnt/PI3K-Akt signaling in gastric cancer.
Zhang C(1), Zhang M(1), Ge S(1), Huang W(1), Lin X(1), Gao J(1), Gong J(1), Shen
L(1).
Author information:
(1)Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and
Translational Research (Ministry of Education/Beijing), Peking University Cancer
Hospital & Institute, Beijing, China.
BACKGROUND: As the most abundant epigenetic modification on mRNAs and long
non-coding RNAs, N6-methyladenosine (m6A) modification extensively exists in
mammalian cells. Controlled by writers (methyltransferases), readers (signal
transducers), and erasers (demethylases), m6A influences mRNA structure,
maturation, and stability, thus negatively regulating protein expression in a
post-translational manner. Nevertheless, current understanding of m6A's roles in
tumorigenesis, especially in gastric cancer (GC) remains to be unveiled. In this
study, we assessed m6A's clinicopathological relevance to GC and explored the
underlying mechanisms.
METHODS: By referring to a proteomics-based GC cohort we previously generated
and the TCGA-GC cohort, we merged expressions of canonical m6A writers
(METTL3/METTL14), readers (YTHDF1/YTHDF2/YTHDF3), and erasers (ALKBH5/FTO),
respectively, as W, R, and E signatures to represent m6A modification. We
stratified patients according to these signatures to decipher m6A's associations
with crucial mutations, prognosis, and clinical indexes. m6A's biological
functions in GC were predicted by gene set enrichment analysis (GSEA) and
validated by in vitro experiments.
RESULTS: We discovered that W and R were potential tumor suppressive signatures,
while E was a potential oncogenic signature in GC. According to W/R/E
stratifications, patients with low m6A-indications were accompanied with higher
mutations of specific genes (CDH1, AR, GLI3, SETBP1, RHOA, MUC6, and TP53) and
also demonstrated adverse clinical outcomes. GSEA suggested that reduced m6A was
correlated with oncogenic signaling and phenotypes. Through in vitro
experiments, we proved that m6A suppression (represented by METTL14 knockdown)
promoted GC cell proliferation and invasiveness through activating Wnt and
PI3K-Akt signaling, while m6A elevation (represented by FTO knockdown) reversed
these phenotypical and molecular changes. m6A may also be involved in interferon
signaling and immune responses of GC.
CONCLUSIONS: Our work demonstrated that low-m6A signatures predicted adverse
clinicopathological features of GC, while the reduction of RNA m6A methylation
activated oncogenic Wnt/PI3K-Akt signaling and promoted malignant phenotypes of
GC cells.
© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
DOI: 10.1002/cam4.2360
PMCID: PMC6712480
PMID: 31243897 [Indexed for MEDLINE]
Conflict of interest statement: The authors report no conflicts of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/36291504
|
1. Children (Basel). 2022 Oct 17;9(10):1568. doi: 10.3390/children9101568.
Effectiveness of Non-Pharmacological Methods, Such as Breastfeeding, to Mitigate
Pain in NICU Infants.
Koukou Z(1), Theodoridou A(1), Taousani E(1), Antonakou A(1), Panteris E(2),
Papadopoulou SS(1), Skordou A(1), Sifakis S(3).
Author information:
(1)School of Health Sciences, International Hellenic University (IHU), 57400
Sindos Thessaloniki, Greece.
(2)Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle
University of Thessaloniki, 54124 Thessaloniki, Greece.
(3)Department of Obstetrics and Gynecology, Mitera Hospital, 71202 Heraklion,
Greece.
Neonates do experience pain and its management is necessary in order to prevent
long-term, as well as, short-term effects. The most common source of pain in the
neonatal intensive care unit (NICU) is caused by medically invasive procedures.
NICU patients have to endure trauma, medical adhesive related skin injuries,
heel lance, venipuncture and intramuscular injection as well as nasogastric
catheterization besides surgery. A cornerstone in pain assessment is the use of
scales such as COMFORT, PIPP-R, NIPS and N-PASS. This narrative review provides
an up to date account of neonate pain management used in NICUs worldwide
focusing on non-pharmacological methods. Non-steroidal anti-inflammatory drugs
have well established adverse side effects and opioids are addictive thus
pharmacological methods should be avoided if possible at least for mild pain
management. Non-pharmacological interventions, particularly breastfeeding and
non-nutritive sucking as primary strategies for pain management in neonates are
useful strategies to consider. The best non-pharmacological methods are
breastfeeding followed by non-nutritive sucking coupled with sucrose sucking.
Regrettably most parents used only physical methods and should be trained and
involved for best results. Further research in NICU is essential as the
developmental knowledge changes and neonate physiology is further uncovered
together with its connection to pain.
DOI: 10.3390/children9101568
PMCID: PMC9600280
PMID: 36291504
Conflict of interest statement: The authors declare no conflict of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/35868358
|
1. J Control Release. 2022 Sep;349:1045-1051. doi: 10.1016/j.jconrel.2022.05.061.
Epub 2022 Sep 8.
Suprachoroidal delivery enables targeting, localization and durability of small
molecule suspensions.
Kansara VS(1), Hancock SE(1), Muya LW(1), Ciulla TA(2).
Author information:
(1)Clearside Biomedical Inc., 900 North Point Parkway, Suite 200, Alpharetta, GA
30005, United States of America.
(2)Clearside Biomedical Inc., 900 North Point Parkway, Suite 200, Alpharetta, GA
30005, United States of America. Electronic address:
[email protected].
Drug delivery to the suprachoroidal space (SCS®) has become a clinical reality
after the 2021 FDA approval of CLS-TA, a triamcinolone acetonide injectable
suspension for suprachoroidal use (XIPERE®), administered via a
microneedle-based device, the SCS Microinjector®. Suprachoroidal (SC) delivery
facilitates targeting, compartmentalization, and durability of small molecule
suspensions, thereby potentially addressing some of the efficacy, safety, and
treatment burden limitations of current retinal therapies. Herein, the design
features of the SCS Microinjector are reviewed, along with the biomechanics of
SC drug delivery. Also presented are preclinical evaluations of SC small
molecule suspensions from 4 different therapeutic classes (plasma kallikrein
inhibitor, receptor tyrosine kinase inhibitor, corticosteroid, complement factor
D inhibitor), highlighting their potential for durability, targeted
compartmentalization, and acceptable safety profiles following
microinjector-based SC delivery. The clinical evaluations of the safety,
tolerability and efficacy of SC delivered triamcinolone further supports
potential of SC small molecule suspensions as a clinically viable strategy for
the treatment of chorioretinal diseases. Also highlighted are current
limitations, key pharmacological considerations, and future opportunities to
optimize the SC microinjector platform for safe, effective, and potentially
long-acting drug delivery for the treatment of chorioretinal disorders.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jconrel.2022.05.061
PMID: 35868358 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34983147
|
1. J Coll Physicians Surg Pak. 2022 Jan;32(1):46-50. doi:
10.29271/jcpsp.2022.01.46.
Does Interval between Breastfeedıng and Heel Lance Affect the Perception of Pain
in Newborns?
Altuntas N(1), Altuntas S(2), Nar D(3), Simsek M(1), Unsal A(1), Gungor AA(3).
Author information:
(1)Department of Pediatrics, Division of Neonatology, Ankara Yıldırım Beyazıt
University Medical Faculty, Yenimahalle Training and Research Hospital, Ankara,
Turkey.
(2)Yuksek Ihtisas University Medical Faculty, Ankara, Turkey.
(3)Ankara Yildirim Beyazit University Medical Faculty, Ankara, Turkey.
OBJECTIVE: To investigate whether the duration between breastfeeding and heel
lance has an effect on babies' pain perception.
STUDY DESIGN: A randomised trial.
PLACE AND DURATION OF STUDY: Obstetrics & Gynecology Unit, Yenimahalle Training
and Research Hospital, Ankara, Turkey between August 2019 and February 2020.
METHODOLOGY: Healthy term newborns who were scheduled for a heel lance blood
collection for newborn screening were included in the study. Healthy term babies
were randomised into three groups, according to their heel lance time. The
procedure was performed immediately after breastfeeding (group 1), one hour
after breastfeeding (group 2), and two hours after breastfeeding (group 3). The
magnitude of pain was measured by the neonatal pain, agitation and sedation
scale (N-PASS) one minute before intervention, at the time of intervention, and
at 1, 2 and 5 minutes after the intervention. Total crying times of the babies
was recorded as well.
RESULTS: Ninety-one babies were included in the study. The pain scores during
heel lance and one and two minutes after heel lance were significantly higher in
group 3 than in group 1 and group 2. Total crying time of the babies in group 3
was also significantly longer than the total crying time of the babies in group
1 and group 2. However, there was no significant difference between group 1 and
2 in terms of pain scores.
CONCLUSION: The duration between breastfeeding and heel lance may influence the
perception of pain in newborns. Keeping this period short, may reduce the
perception of pain. Key Words: Breastfeeding, Breast milk, Newborn, Pain.
DOI: 10.29271/jcpsp.2022.01.46
PMID: 34983147 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34871187
|
1. Curr Opin HIV AIDS. 2022 Jan 1;17(1):15-21. doi: 10.1097/COH.0000000000000713.
Lenacapavir: a first-in-class HIV-1 capsid inhibitor.
Dvory-Sobol H(1), Shaik N, Callebaut C, Rhee MS.
Author information:
(1)Gilead Sciences, Foster City, California, USA.
PURPOSE OF REVIEW: This review summarizes available data for lenacapavir, an
investigational first-in-class agent that disrupts functioning of HIV capsid
protein across multiple steps in the viral life cycle.
RECENT FINDINGS: Lenacapavir demonstrated picomolar potency in vitro with no
cross resistance to existing antiretroviral classes and potent antiviral
activity in persons with HIV-1. In persons with HIV-1, there was no preexisting
resistance to lenacapavir regardless of treatment history. Lenacapavir can be
administered orally either daily or weekly and subcutaneously up to every
6 months. In heavily treatment-experienced persons with multidrug-resistant
HIV-1 and in treatment-naive persons with HIV-1, lenacapavir in combination with
other antiretroviral agents led to high rates of virologic suppression and was
well tolerated.
SUMMARY: Ongoing studies are evaluating long-acting dosing of lenacapavir for
treating HIV-1 in combination with other antiretrovirals and preventing HIV-1 as
a single agent.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/COH.0000000000000713
PMID: 34871187 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35620884
|
1. Int J Nurs Pract. 2022 Dec;28(6):e13067. doi: 10.1111/ijn.13067. Epub 2022 May
27.
The effect of breastfeeding, breast milk odour and mother's heartbeat sound on
pain level in newborns: A randomized trial.
Tavlar M(1), Karakoc A(1).
Author information:
(1)Department of Midwifery, Instıtute of Health Science, Marmara University,
Istanbul, Turkey.
AIM: This study aimed to compare the effects of breastfeeding, breast milk odour
and mother's heartbeat sounds on perceived pain during heel lance procedures in
term newborns.
DESIGN: This was a randomized three-group experimental study.
METHODS: The sample of the study consisted of 90 newborns. The data were
collected using pulse oximeter, fetal hand doppler, voice recorder, loudspeaker,
a data collection form and the ALPS-Neo Pain and Stress Assessment Scale for
Newborn Infants.
RESULTS: During the procedure, newborns in the breast milk odour group had high
levels of pain and stress, those in the mother's heartbeat sounds group had mild
pain and stress, and those in the breastfeeding group had no pain and stress.
Additionally, a statistically significant difference was found between their
crying times. This difference was the highest for newborns in the breast milk
odour group, followed by the mother's heartbeat sounds and breastfeeding groups,
respectively.
CONCLUSION: Breastfeeding and mother's heartbeat sounds, which are
non-pharmacological pain relief methods, are effective in neonatal pain
management. However, breast milk odour is not effective for pain control in
newborns. Further studies should examine the efficacy combinations of these
methods.
© 2022 John Wiley & Sons Australia, Ltd.
DOI: 10.1111/ijn.13067
PMID: 35620884 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36272024
|
1. Drugs. 2022 Sep;82(14):1499-1504. doi: 10.1007/s40265-022-01786-0.
Lenacapavir: First Approval.
Paik J(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. [email protected].
Erratum in
Drugs. 2023 Jul;83(11):1061. doi: 10.1007/s40265-023-01908-2.
Lenacapavir (Sunlenca®) is a long-acting capsid inhibitor of human
immunodeficiency virus type 1 (HIV-1) being developed by Gilead Sciences Inc. It
is available as an oral tablet and injectable solution, with the latter being a
slow-release formulation to allow bi-annual subcutaneous administration. In
August 2022, lenacapavir received its first approval in the EU for use in
combination with other antiretroviral(s) in adults with multi-drug resistant HIV
infection, for whom it is otherwise not possible to construct a suppressive
anti-viral regimen. This article summarizes the milestones in the development of
lenacapavir leading to this first approval for the treatment of HIV-1 infection.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01786-0
PMCID: PMC10267266
PMID: 36272024 [Indexed for MEDLINE]
Conflict of interest statement: During the peer review process the manufacturer
of the agent under review was offered an opportunity to comment on the article.
Changes resulting from any comments received were made by the authors on the
basis of scientific completeness and accuracy. Julia Paik is a salaried employee
of Adis International Ltd/Springer Nature, and declares no relevant conflicts of
interest. All authors contributed to the review and are responsible for the
article content.
|
http://www.ncbi.nlm.nih.gov/pubmed/17375185
|
1. PLoS One. 2007 Mar 21;2(3):e299. doi: 10.1371/journal.pone.0000299.
Multiple-color optical activation, silencing, and desynchronization of neural
activity, with single-spike temporal resolution.
Han X(1), Boyden ES.
Author information:
(1)Stanford University School of Medicine, Stanford, California, United States
of America.
The quest to determine how precise neural activity patterns mediate computation,
behavior, and pathology would be greatly aided by a set of tools for reliably
activating and inactivating genetically targeted neurons, in a temporally
precise and rapidly reversible fashion. Having earlier adapted a light-activated
cation channel, channelrhodopsin-2 (ChR2), for allowing neurons to be stimulated
by blue light, we searched for a complementary tool that would enable optical
neuronal inhibition, driven by light of a second color. Here we report that
targeting the codon-optimized form of the light-driven chloride pump
halorhodopsin from the archaebacterium Natronomas pharaonis (hereafter
abbreviated Halo) to genetically-specified neurons enables them to be silenced
reliably, and reversibly, by millisecond-timescale pulses of yellow light. We
show that trains of yellow and blue light pulses can drive high-fidelity
sequences of hyperpolarizations and depolarizations in neurons simultaneously
expressing yellow light-driven Halo and blue light-driven ChR2, allowing for the
first time manipulations of neural synchrony without perturbation of other
parameters such as spiking rates. The Halo/ChR2 system thus constitutes a
powerful toolbox for multichannel photoinhibition and photostimulation of
virally or transgenically targeted neural circuits without need for exogenous
chemicals, enabling systematic analysis and engineering of the brain, and
quantitative bioengineering of excitable cells.
DOI: 10.1371/journal.pone.0000299
PMCID: PMC1808431
PMID: 17375185 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/22815873
|
1. PLoS One. 2012;7(7):e40937. doi: 10.1371/journal.pone.0040937. Epub 2012 Jul
16.
Microbial light-activatable proton pumps as neuronal inhibitors to functionally
dissect neuronal networks in C. elegans.
Husson SJ(1), Liewald JF, Schultheis C, Stirman JN, Lu H, Gottschalk A.
Author information:
(1)Buchmann Institute for Molecular Life Sciences, Johann Wolfgang
Goethe-University Frankfurt, Frankfurt am Main, Germany.
[email protected]
Essentially any behavior in simple and complex animals depends on neuronal
network function. Currently, the best-defined system to study neuronal circuits
is the nematode Caenorhabditis elegans, as the connectivity of its 302 neurons
is exactly known. Individual neurons can be activated by photostimulation of
Channelrhodopsin-2 (ChR2) using blue light, allowing to directly probe the
importance of a particular neuron for the respective behavioral output of the
network under study. In analogy, other excitable cells can be inhibited by
expressing Halorhodopsin from Natronomonas pharaonis (NpHR) and subsequent
illumination with yellow light. However, inhibiting C. elegans neurons using
NpHR is difficult. Recently, proton pumps from various sources were established
as valuable alternative hyperpolarizers. Here we show that archaerhodopsin-3
(Arch) from Halorubrum sodomense and a proton pump from the fungus Leptosphaeria
maculans (Mac) can be utilized to effectively inhibit excitable cells in C.
elegans. Arch is the most powerful hyperpolarizer when illuminated with yellow
or green light while the action spectrum of Mac is more blue-shifted, as
analyzed by light-evoked behaviors and electrophysiology. This allows these
tools to be combined in various ways with ChR2 to analyze different subsets of
neurons within a circuit. We exemplify this by means of the polymodal aversive
sensory ASH neurons, and the downstream command interneurons to which ASH
neurons signal to trigger a reversal followed by a directional turn.
Photostimulating ASH and subsequently inhibiting command interneurons using
two-color illumination of different body segments, allows investigating temporal
aspects of signaling downstream of ASH.
DOI: 10.1371/journal.pone.0040937
PMCID: PMC3397962
PMID: 22815873 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/21483674
|
1. PLoS One. 2011 Apr 5;6(4):e18452. doi: 10.1371/journal.pone.0018452.
Selective optical control of synaptic transmission in the subcortical visual
pathway by activation of viral vector-expressed halorhodopsin.
Kaneda K(1), Kasahara H, Matsui R, Katoh T, Mizukami H, Ozawa K, Watanabe D, Isa
T.
Author information:
(1)Department of Developmental Physiology, National Institute for Physiological
Sciences, Okazaki, Japan. [email protected]
The superficial layer of the superior colliculus (sSC) receives visual inputs
via two different pathways: from the retina and the primary visual cortex.
However, the functional significance of each input for the operation of the sSC
circuit remains to be identified. As a first step toward understanding the
functional role of each of these inputs, we developed an optogenetic method to
specifically suppress the synaptic transmission in the retino-tectal pathway. We
introduced enhanced halorhodopsin (eNpHR), a yellow light-sensitive,
membrane-targeting chloride pump, into mouse retinal ganglion cells (RGCs) by
intravitreously injecting an adeno-associated virus serotype-2 vector carrying
the CMV-eNpHR-EYFP construct. Several weeks after the injection, whole-cell
recordings made from sSC neurons in slice preparations revealed that yellow
laser illumination of the eNpHR-expressing retino-tectal axons, putatively
synapsing onto the recorded cells, effectively inhibited EPSCs evoked by
electrical stimulation of the optic nerve layer. We also showed that sSC spike
activities elicited by visual stimulation were significantly reduced by laser
illumination of the sSC in anesthetized mice. These results indicate that
photo-activation of eNpHR expressed in RGC axons enables selective blockade of
retino-tectal synaptic transmission. The method established here can most likely
be applied to a variety of brain regions for studying the function of individual
inputs to these regions.
DOI: 10.1371/journal.pone.0018452
PMCID: PMC3071716
PMID: 21483674 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/23637949
|
1. PLoS One. 2013 Apr 24;8(4):e62013. doi: 10.1371/journal.pone.0062013. Print
2013.
Optogenetic delay of status epilepticus onset in an in vivo rodent epilepsy
model.
Sukhotinsky I(1), Chan AM, Ahmed OJ, Rao VR, Gradinaru V, Ramakrishnan C,
Deisseroth K, Majewska AK, Cash SS.
Author information:
(1)Department of Neurology, Massachusetts General Hospital and Harvard Medical
School, Boston, Massachusetts, United States of America.
Epilepsy is a devastating disease, currently treated with medications, surgery
or electrical stimulation. None of these approaches is totally effective and our
ability to control seizures remains limited and complicated by frequent side
effects. The emerging revolutionary technique of optogenetics enables
manipulation of the activity of specific neuronal populations in vivo with
exquisite spatiotemporal resolution using light. We used optogenetic approaches
to test the role of hippocampal excitatory neurons in the lithium-pilocarpine
model of acute elicited seizures in awake behaving rats. Hippocampal pyramidal
neurons were transduced in vivo with a virus carrying an enhanced halorhodopsin
(eNpHR), a yellow light activated chloride pump, and acute seizure progression
was then monitored behaviorally and electrophysiologically in the presence and
absence of illumination delivered via an optical fiber. Inhibition of those
neurons with illumination prior to seizure onset significantly delayed
electrographic and behavioral initiation of status epilepticus, and altered the
dynamics of ictal activity development. These results reveal an essential role
of hippocampal excitatory neurons in this model of ictogenesis and illustrate
the power of optogenetic approaches for elucidation of seizure mechanisms. This
early success in controlling seizures also suggests future therapeutic avenues.
DOI: 10.1371/journal.pone.0062013
PMCID: PMC3634849
PMID: 23637949 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/28650460
|
1. Nat Biotechnol. 2017 Sep;35(9):858-863. doi: 10.1038/nbt.3902. Epub 2017 Jun
26.
A calcium- and light-gated switch to induce gene expression in activated
neurons.
Lee D(1)(2)(3), Hyun JH(1), Jung K(1), Hannan P(1), Kwon HB(1)(4).
Author information:
(1)Max Planck Florida Institute for Neuroscience, Jupiter, Florida, USA.
(2)Department of Anatomy, College of Medicine, Korea University, Seoul, Republic
of Korea.
(3)Department of Biomedical Science, Brain Korea 21 PLUS, College of Medicine,
Korea University, Seoul, Republic of Korea.
(4)Max Planck Institute of Neurobiology, Martinsried, Germany.
Comment in
Nat Chem Biol. 2017 Aug 18;13(9):923. doi: 10.1038/nchembio.2469.
Nat Biotechnol. 2017 Sep 11;35(9):827-828. doi: 10.1038/nbt.3954.
Despite recent advances in optogenetics, it remains challenging to manipulate
gene expression in specific populations of neurons. We present a dual-protein
switch system, Cal-Light, that translates neuronal-activity-mediated calcium
signaling into gene expression in a light-dependent manner. In cultured neurons
and brain slices, we show that Cal-Light drives expression of the reporter EGFP
with high spatiotemporal resolution only in the presence of both blue light and
calcium. Delivery of the Cal-Light components to the motor cortex of mice by
viral vectors labels a subset of excitatory and inhibitory neurons related to
learned lever-pressing behavior. By using Cal-Light to drive expression of the
inhibitory receptor halorhodopsin (eNpHR), which responds to yellow light, we
temporarily inhibit the lever-pressing behavior, confirming that the labeled
neurons mediate the behavior. Thus, Cal-Light enables dissection of neural
circuits underlying complex mammalian behaviors with high spatiotemporal
precision.
DOI: 10.1038/nbt.3902
PMID: 28650460 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/27905012
|
1. Mol Neurobiol. 2017 Dec;54(10):8211-8224. doi: 10.1007/s12035-016-0279-3. Epub
2016 Dec 1.
Microbial Proteins as Novel Industrial Biotechnology Hosts to Treat Epilepsy.
Amtul Z(1), Aziz AA(2).
Author information:
(1)Dr. Panjwani Center for Molecular Medicine and Drug Research, International
Center for Chemical and Biological Sciences, University of Karachi, Karachi,
75270, Pakistan. [email protected].
(2)Sir Wilfrid Laurier Secondary School, Thames Valley District School Board,
N6C 4W7, London, ON, Canada.
Epilepsy is characterized by the hyperexcitability of various neuronal circuits
that results due to the imbalance between glutamate-mediated excitation of
voltage-gated cation channels and γ-amino butyric acid (GABA)-mediated
inhibition of anion channels leading to aberrant, sporadic oscillations or
fluctuations in neuronal electrical activity. Epilepsy with a risk of mortality
and around 65 million sufferers of all ages all over the world is limited
therapeutically with high rates of adverse reactions, lack of complete seizure
control, and over 30% patients with refractory epilepsy. The only alternative to
medicines is to identify and surgically remove the seizure foci in the brain or
to abort the seizures just as they begin using an implanted cerebral electrode.
However, these alternatives are unable to precisely aim aberrant neuronal
circuits while leaving others unaltered. Epilepsy animal models also constitute
the identical constraint. Thus, a better target-specific approach is needed to
study and treat epilepsy. Unicellular green algae Chlamydomonas reinhardtii
expresses a channelrhodopsin-2 (ChR2) sodium ion channel protein that controls
the phototaxis movement of algae in response to blue light. Similarly, archaeon
Natronomonas pharaonis (NpHR) expresses a monovalent Cl- channel protein
halorhodopsin that responds to yellow light. These features of ChR2 and NpHR
proteins can be used in optogenetic techniques to manipulate the bi-directional
firing pattern of neuronal circuits in an attempt to better understand the
pathophysiology of epileptic seizures as well as to discover novel potential
drugs to treat epilepsy.
DOI: 10.1007/s12035-016-0279-3
PMID: 27905012 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23366158
|
1. Annu Int Conf IEEE Eng Med Biol Soc. 2012;2012:1386-9. doi:
10.1109/EMBC.2012.6346197.
Cardiac optogenetics.
Abilez OJ(1).
Author information:
(1)Bio-X Program, Stanford University, Stanford, CA 94305, USA.
[email protected]
For therapies based on human induced pluripotent stem cell (hiPSC)-derived
cardiomyocytes (CM) to be effective, arrhythmias must be avoided. Towards
achieving this goal, light-activated channelrhodopsin-2 (ChR2), a cation channel
activated with 480 nm light, and a first generation halorhodopsin (NpHR1.0), an
anion pump activated by 580 nm light, have been introduced into hiPSC. By using
in vitro approaches, hiPSC-CM are able to be optogenetically activated and
inhibited. ChR2 and NpHR1.0 are stably transduced into undifferentiated hiPSC
via a lentiviral vector. Via directed differentiation, both wildtype hiPSC-CM
(hiPSC(WT)-CM) and hiPSC(ChR2/NpHR)-CM are produced and subjected to both
electrical and optical stimulation. Both hiPSC(WT)-CM and hiPSC(ChR2/NpHR)-CM
respond to traditional electrical stimulation and produce similar contractility
features but only hiPSC(ChR2/NpHR)-CM can be synchronized and inhibited by
optical stimulation. Here it is shown that light sensitive proteins can enable
in vitro optical control of hiPSC-CM. For future therapy, in vivo optical
stimulation could allow precise and specific synchronization of implanted
hiPSC-CM with patient cardiac rates and rhythms.
DOI: 10.1109/EMBC.2012.6346197
PMID: 23366158 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17123746
|
1. Gene. 2007 Mar 1;389(1):52-65. doi: 10.1016/j.gene.2006.09.029. Epub 2006 Oct
10.
Prevalence of the initiator over the TATA box in human and yeast genes and
identification of DNA motifs enriched in human TATA-less core promoters.
Yang C(1), Bolotin E, Jiang T, Sladek FM, Martinez E.
Author information:
(1)Genetics Genomics and Bioinformatics Graduate Program, University of
California, Riverside, CA 92521, USA.
The core promoter of eukaryotic genes is the minimal DNA region that recruits
the basal transcription machinery to direct efficient and accurate transcription
initiation. The fraction of human and yeast genes that contain specific core
promoter elements such as the TATA box and the initiator (INR) remains unclear
and core promoter motifs specific for TATA-less genes remain to be identified.
Here, we present genome-scale computational analyses indicating that
approximately 76% of human core promoters lack TATA-like elements, have a high
GC content, and are enriched in Sp1-binding sites. We further identify two
motifs - M3 (SCGGAAGY) and M22 (TGCGCANK) - that occur preferentially in human
TATA-less core promoters. About 24% of human genes have a TATA-like element and
their promoters are generally AT-rich; however, only approximately 10% of these
TATA-containing promoters have the canonical TATA box (TATAWAWR). In contrast,
approximately 46% of human core promoters contain the consensus INR (YYANWYY)
and approximately 30% are INR-containing TATA-less genes. Significantly,
approximately 46% of human promoters lack both TATA-like and consensus INR
elements. Surprisingly, mammalian-type INR sequences are present - and tend to
cluster - in the transcription start site (TSS) region of approximately 40% of
yeast core promoters and the frequency of specific core promoter types appears
to be conserved in yeast and human genomes. Gene Ontology analyses reveal that
TATA-less genes in humans, as in yeast, are frequently involved in basic
"housekeeping" processes, while TATA-containing genes are more often highly
regulated, such as by biotic or stress stimuli. These results reveal unexpected
similarities in the occurrence of specific core promoter types and in their
associated biological processes in yeast and humans and point to novel
vertebrate-specific DNA motifs that might play a selective role in
TATA-independent transcription.
DOI: 10.1016/j.gene.2006.09.029
PMCID: PMC1955227
PMID: 17123746 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1736286
|
1. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1060-4. doi:
10.1073/pnas.89.3.1060.
Transcription factor TFIID induces DNA bending upon binding to the TATA element.
Horikoshi M(1), Bertuccioli C, Takada R, Wang J, Yamamoto T, Roeder RG.
Author information:
(1)Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New
York, NY 10021.
The TATA box-binding factor TFIID plays a primary role in the process of
transcription initiation by RNA polymerase II and its regulation by various
gene-specific factors. Here we employ a permuted binding site/gel retardation
assay with recombinant yeast and human TFIID to show that this factor induces
DNA bending around the TATA element. These results are consistent with the
presence of G + C-rich sequence elements flanking the consensus TATA element and
led to the recently confirmed suggestion that TFIID interacts with the TATA
element via the minor groove. They also raise the possibility that TFIID-induced
bending might facilitate promoter interactions of other general factors in the
preinitiation complex or interactions between general transcription factors and
regulatory factors bound at upstream sites.
DOI: 10.1073/pnas.89.3.1060
PMCID: PMC48385
PMID: 1736286 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1409643
|
1. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9372-6. doi:
10.1073/pnas.89.20.9372.
Cloning and chromosomal mapping of a human immunodeficiency virus 1 "TATA"
element modulatory factor.
Garcia JA(1), Ou SH, Wu F, Lusis AJ, Sparkes RS, Gaynor RB.
Author information:
(1)Department of Microbiology and Immunology, University of California, Los
Angeles School of Medicine 90024.
A critical regulatory element in many promoters transcribed by RNA polymerase II
is the "TATA" box, which is located 25-30 nucleotides upstream of the
transcription initiation site. TFIID is a biochemically defined HeLa cell
nuclear fraction containing a transcription factor activity that binds
specifically to the TATA box and is critical in determining both basal and
regulated promoter activity. Recently, the gene for a TATA-binding protein was
cloned and found to bind to various TATA elements and to substitute for TFIID in
stimulating basal gene expression in in vitro transcription systems. However, it
is possible that additional cellular factors can bind to the TATA element and
influence the level of gene expression. By using lambda gt11 expression cloning
with oligonucleotides corresponding to the human immunodeficiency virus 1 TATA
element, we report the identification of a cellular protein with a calculated
molecular mass of 123 kDa that we designate TATA element modulatory factor
(TMF). TMF binds to the human immunodeficiency virus 1 TATA element in
gel-retardation assays and inhibits activation of the viral long terminal repeat
by the TATA-binding protein in in vitro transcription assays. TMF contains
leucine-zipper amino acid motifs and exhibits homology in its DNA binding domain
with the phage-encoded DNA binding protein Ner. Chromosomal mapping localizes
the TMF gene to human chromosome 3p12-p21, which is a site of frequent
rearrangements in lung and renal carcinomas. Thus, TMF is a transcription factor
that likely regulates the expression of both viral and cellular genes.
DOI: 10.1073/pnas.89.20.9372
PMCID: PMC50133
PMID: 1409643 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9383448
|
1. Chem Biol. 1995 Jul;2(7):457-69. doi: 10.1016/1074-5521(95)90263-5.
TBP binding to the TATA box induces a specific downstream unwinding site that is
targeted by pluramycin.
Sun D(1), Hurley LH.
Author information:
(1)Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin
78712-1074, USA.
BACKGROUND: The TATA-binding protein (TBP) is one of the major components of the
human TFIID multiprotein complex. It is important in directing the initiation of
RNA transcription at a site immediately downstream of the TATA sequence (TATA
box) found in many eukaryotic promoters. The crystal structure of TBP complexed
with an oligonucleotide containing the TATA box revealed a protein with an
approximate two-fold symmetry which apparently has symmetrical interactions with
DNA. It is not known how an asymmetric effect involving downstream activation
can be produced by an apparent symmetric complex. We set out to examine the
state of DNA in the TBP-DNA complex using pluramycin, a small molecular weight
probe of DNA accessibility.
RESULTS: Binding of TBP to the TATA box facilitates intercalation of pluramycin
at a defined site immediately downstream of the TATA sequence through an
apparent transient unwinding of the DNA. Pluramycin adducts are detected by the
production of DNA strand breakage products upon heating. Incubation of
pluramycin with the TBP-DNA complex facilitates the trapping of the specific
complex by intercalation. Gel mobility shift and circularization assays reveal
that the binding of pluramycin on the 3'-side of the TATA box region
considerably stabilizes the TBP-DNA complex.
CONCLUSIONS: We propose that the TBP-DNA-pluramycin ternary complex is a
'specific' binding mode in which TBP and pluramycin make compensatory
alterations in DNA, accounting for the improved stability of the ternary
complex. We also propose a model of the ternary complex that explains the
observed asymmetric effect of TBP binding to the TATA box.
DOI: 10.1016/1074-5521(95)90263-5
PMID: 9383448 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23801666
|
1. Wiley Interdiscip Rev Dev Biol. 2012 Jan-Feb;1(1):40-51. doi: 10.1002/wdev.21.
Epub 2011 Dec 6.
Perspectives on the RNA polymerase II core promoter.
Kadonaga JT(1).
Author information:
(1)Department of Molecular Biology, University of California, San Diego, La
Jolla, CA, USA. [email protected]
The RNA polymerase II core promoter is sometimes referred to as the gateway to
transcription. The core promoter is generally defined to be the stretch of DNA
that directs the initiation of transcription. This simple description belies a
complex multidimensional regulatory element, as there is considerable diversity
in core promoter structure and function. Core promoters can be viewed at the
levels of DNA sequences, transcription factors, and biological networks. Key DNA
sequences are known as core promoter elements, which include the TATA box,
initiator (Inr), polypyrimidine initiator (TCT), TFIIB recognition element
(BRE), motif ten element (MTE), and downstream core promoter element (DPE)
motifs. There are no universal core promoter elements that are present in all
promoters. Different types of core promoters are transcribed by different sets
of transcription factors and exhibit distinct properties, such as specific
interactions with transcriptional enhancers, that are determined by the presence
or absence of particular core promoter motifs. Moreover, some core promoter
elements have been found to be associated with specific biological networks. For
instance, the TCT motif is dedicated to the transcription of ribosomal protein
genes in Drosophila and humans. In addition, nearly all of the Drosophila Hox
genes have a DPE motif in their core promoters. The complexity of the core
promoter is further seen in the relation among transcription initiation
patterns, the stability or lability of transcriptional states, and the
organization of the chromatin structure in the promoter region. Hence, the
current data indicate that the core promoter is a critical component in the
regulation of gene activity.
Copyright © 2011 Wiley Periodicals, Inc.
DOI: 10.1002/wdev.21
PMCID: PMC3695423
PMID: 23801666 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8507207
|
1. Biochem Biophys Res Commun. 1993 May 14;192(3):1432-8. doi:
10.1006/bbrc.1993.1576.
Underwinding of DNA on binding of yeast TFIID to the TATA element.
Tabuchi H(1), Handa H, Hirose S.
Author information:
(1)Department of Developmental Genetics, National Institute of Genetics,
Mishima, Japan.
The TATA box-binding factor TFIID is an essential component for the initiation
of transcription by eukaryotic RNA polymerase II. We investigated the effect of
DNA supercoiling on TFIID: promoter interactions using recombinant yeast (ry)
TFIID. DNase I footprinting analysis showed that ryTFIID has a higher affinity
for the adenovirus major late promoter in the negatively supercoiled state than
that in the relaxed state. On the contrary, its affinity for the Drosophila
hsp70 promoter is constant irrespective of DNA topology. Binding of ryTFIID to
these promoters induced underwinding of duplex DNA. The functional TATA box and
active ryTFIID are essential for the underwinding. The step was facilitated by
negative supercoiling of DNA on the adenovirus major late promoter but not on
the Drosophila hsp70 promoter.
DOI: 10.1006/bbrc.1993.1576
PMID: 8507207 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16522199
|
1. BMC Bioinformatics. 2006 Mar 7;7:114. doi: 10.1186/1471-2105-7-114.
Genome-wide analysis of core promoter elements from conserved human and mouse
orthologous pairs.
Jin VX(1), Singer GA, Agosto-Pérez FJ, Liyanarachchi S, Davuluri RV.
Author information:
(1)Human Cancer Genetics Program, Comprehensive Cancer Center, Department of
Molecular Virology, Immunology, and Medical Genetics, The Ohio State University,
Columbus, OH 43210, USA. [email protected]
BACKGROUND: The canonical core promoter elements consist of the TATA box,
initiator (Inr), downstream core promoter element (DPE), TFIIB recognition
element (BRE) and the newly-discovered motif 10 element (MTE). The motifs for
these core promoter elements are highly degenerate, which tends to lead to a
high false discovery rate when attempting to detect them in promoter sequences.
RESULTS: In this study, we have performed the first analysis of these core
promoter elements in orthologous mouse and human promoters with
experimentally-supported transcription start sites. We have identified these
various elements using a combination of positional weight matrices (PWMs) and
the degree of conservation of orthologous mouse and human sequences--a procedure
that significantly reduces the false positive rate of motif discovery. Our
analysis of 9,010 orthologous mouse-human promoter pairs revealed two
combinations of three-way synergistic effects, TATA-Inr-MTE and BRE-Inr-MTE. The
former has previously been putatively identified in human, but the latter
represents a novel synergistic relationship.
CONCLUSION: Our results demonstrate that DNA sequence conservation can greatly
improve the identification of functional core promoter elements in the human
genome. The data also underscores the importance of synergistic occurrence of
two or more core promoter elements. Furthermore, the sequence data and results
presented here can help build better computational models for predicting the
transcription start sites in the promoter regions, which remains one of the most
challenging problems.
DOI: 10.1186/1471-2105-7-114
PMCID: PMC1475891
PMID: 16522199 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9618449
|
1. Microbiol Mol Biol Rev. 1998 Jun;62(2):465-503. doi:
10.1128/MMBR.62.2.465-503.1998.
Molecular genetics of the RNA polymerase II general transcriptional machinery.
Hampsey M(1).
Author information:
(1)Department of Biochemistry, Division of Nucleic Acids Enzymology, Robert Wood
Johnson Medical School, University of Medicine and Dentistry of New Jersey,
Piscataway, New Jersey 08854-5635, USA. [email protected]
Transcription initiation by RNA polymerase II (RNA pol II) requires interaction
between cis-acting promoter elements and trans-acting factors. The eukaryotic
promoter consists of core elements, which include the TATA box and other DNA
sequences that define transcription start sites, and regulatory elements, which
either enhance or repress transcription in a gene-specific manner. The core
promoter is the site for assembly of the transcription preinitiation complex,
which includes RNA pol II and the general transcription fctors TBP, TFIIB,
TFIIE, TFIIF, and TFIIH. Regulatory elements bind gene-specific factors, which
affect the rate of transcription by interacting, either directly or indirectly,
with components of the general transcriptional machinery. A third class of
transcription factors, termed coactivators, is not required for basal
transcription in vitro but often mediates activation by a broad spectrum of
activators. Accordingly, coactivators are neither gene-specific nor general
transcription factors, although gene-specific coactivators have been described
in metazoan systems. Transcriptional repressors include both gene-specific and
general factors. Similar to coactivators, general transcriptional repressors
affect the expression of a broad spectrum of genes yet do not repress all genes.
General repressors either act through the core transcriptional machinery or are
histone related and presumably affect chromatin function. This review focuses on
the global effectors of RNA polymerase II transcription in yeast, including the
general transcription factors, the coactivators, and the general repressors.
Emphasis is placed on the role that yeast genetics has played in identifying
these factors and their associated functions.
DOI: 10.1128/MMBR.62.2.465-503.1998
PMCID: PMC98922
PMID: 9618449 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8502653
|
1. Proc Soc Exp Biol Med. 1993 Jun;203(2):127-39. doi:
10.3181/00379727-203-43583.
Site-specific initiation of transcription by RNA polymerase II.
Kollmar R(1), Farnham PJ.
Author information:
(1)Program in Cell and Molecular Biology, University of Wisconsin, Madison
53706.
RNA polymerase II initiates transcription at specific DNA sequences. Studies
using sequence analysis and molecular genetics suggest a simple and universal
model of start-site selection by RNA polymerase II. Two consensus sequences
occur at fixed positions in promoters from higher eukaryotes and their viruses:
the TATA box around -30 and the initiator at the start site of transcription.
Both consensus sequences function as positioning elements that control
site-specific initiation. As a first step during initiation, the basal
transcription factor TFIID binds to the TATA box; regulatory transcription
factors can tether TFIID bind to the TATA box; regulatory transcription factors
can tether TFIID to promoters without a consensus TATA box. TFIID then directs
the assembly of other basal transcription factors and RNA polymerase II into a
preinitiation complex. Finally, RNA polymerase II searches for the best match to
the initiator consensus about 30 base pairs downstream of the TATA box to select
the exact start site. The transcriptional activity of a start-site sequence
generally correlates with its similarity to the initiator consensus, suggesting
that there is only one type of initiator.
DOI: 10.3181/00379727-203-43583
PMID: 8502653 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2197561
|
1. Nature. 1990 Jul 26;346(6282):390-4. doi: 10.1038/346390a0.
Arabidopsis thaliana contains two genes for TFIID.
Gasch A(1), Hoffmann A, Horikoshi M, Roeder RG, Chua NH.
Author information:
(1)Laboratory of Plant Molecular Biology, Rockefeller University, New York, New
York 1021-6399.
The general transcription initiation factor TFIID plays a primary part in the
activation of eukaryotic genes transcribed by RNA polymerase II. Binding of
TFIID to the TATA box initiates the assembly of other general transcription
factors as well as RNA polymerase II at the promoter resulting in a
preinitiation complex capable of accurate transcription initiation in vitro.
Human TFIID has been shown to interact with various regulatory factors. The
observation that stimulation of transcription by different trans-acting factors
is mediated through distinct TATA elements led to the suggestion that different
types of TFIID may exist in yeast, humans and plants. Here we report the cloning
and characterization of two distinct TFIID complementary DNA clones from
Arabidopsis thaliana. Furthermore, we have found that TFIID from Arabidopsis and
other organisms shows homology to helix-loop-helix proteins.
DOI: 10.1038/346390a0
PMID: 2197561 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7729424
|
1. EMBO J. 1995 Apr 3;14(7):1490-7. doi: 10.1002/j.1460-2075.1995.tb07135.x.
TBP mutants defective in activated transcription in vivo.
Arndt KM(1), Ricupero-Hovasse S, Winston F.
Author information:
(1)Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
The TATA box binding protein (TBP) plays a central and essential role in
transcription initiation. At TATA box-containing genes transcribed by RNA
polymerase II, TBP binds to the promoter and initiates the assembly of a
multiprotein preinitiation complex. Several studies have suggested that binding
of TBP to the TATA box is an important regulatory step in transcription
initiation in vitro. To determine whether TBP is a target of regulatory factors
in vivo, we performed a genetic screen in yeast for TBP mutants defective in
activated transcription. One class of TBP mutants identified in this screen
comprises inositol auxotrophs that are also defective in using galactose as a
carbon source. These phenotypes are due to promoter-specific defects in
transcription initiation that are governed by the upstream activating sequence
(UAS) and apparently not by the sequence of the TATA element. The finding that
these TBP mutants are severely impaired in DNA binding in vitro suggests that
transcription initiation at certain genes is regulated at the level of TATA box
binding by TBP in vivo.
DOI: 10.1002/j.1460-2075.1995.tb07135.x
PMCID: PMC398236
PMID: 7729424 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29624723
|
1. Mov Disord. 2018 Jul;33(6):1000-1005. doi: 10.1002/mds.27353. Epub 2018 Apr 6.
Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's
ataxia.
Zesiewicz T(1), Heerinckx F(2), De Jager R(2), Omidvar O(3), Kilpatrick M(4),
Shaw J(1), Shchepinov MS(2).
Author information:
(1)Department of Neurology, University of South Florida, Tampa, Florida, USA.
(2)Retrotope, Inc., Los Altos, California, USA.
(3)Collaborative Neuroscience Network, Long Beach, California, USA.
(4)College of Education, University of South Florida, Tampa, Florida, USA.
BACKGROUND: RT001 is a deuterated ethyl linoleate that inhibits lipid
peroxidation and is hypothesized to reduce cellular damage and recover
mitochondrial function in degenerative diseases such as Friedreich's ataxia.
OBJECTIVE: To evaluate the safety, pharmacokinetics, and preliminary efficacy of
RT001 in Friedreich's ataxia patients.
DESIGN/METHODS: We conducted a phase I/II double-blind, comparator-controlled
trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each
cohort). Subjects were randomized 2:1 to receive either RT001 (1.8 or 9.0
g/day), or a matching dose of nondeuterated ethyl linoleate as comparator for 28
days. The primary endpoints were safety, tolerability, and pharmacokinetic
analysis. Secondary endpoints included cardiopulmonary exercise testing and
timed 25-foot walk.
RESULTS: Nineteen patients enrolled in the trial, and 18 completed all safety
and efficacy measurements. RT001 was found to be safe and tolerable, with plasma
levels approaching saturation by 28 days. One subject with a low body mass index
experienced steatorrhea taking a high dose and discontinued the study.
Deuterated arachidonic acid (a brain-penetrant metabolite of RT001) was found to
be present in plasma on day 28. There was an improvement in peak workload in the
drug group compared to placebo (0.16 watts/kg; P = 0.008), as well as an
improvement trend in peak oxygen consumption (change of 0.16 L/min; P = 0.116),
and in stride speed (P = 0.15).
CONCLUSIONS: RT001 was found to be safe and tolerable over 28 days, and improved
peak workload. Further research into the effect of RT001 in Friedreich's ataxia
is warranted. © 2018 International Parkinson and Movement Disorder Society.
© 2018 International Parkinson and Movement Disorder Society.
DOI: 10.1002/mds.27353
PMID: 29624723 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34315378
|
1. Curr Neuropharmacol. 2021;19(12):2276-2295. doi:
10.2174/1570159X19666210726151924.
Promising Perspective to Facioscapulohumeral Muscular Dystrophy Treatment:
Nutraceuticals and Phytochemicals.
Hangül C(1), Karaüzüm SB(1), Akkol EK(2), Demir-Dora D(3), Çetin Z(4), Saygılı
Eİ(5), Evcili G(6), Sobarzo-Sánchez E(7).
Author information:
(1)Department of Medical Biology, Faculty of Medicine, Akdeniz University,
Antalya, Turkey.
(2)Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330,
Ankara, Turkey.
(3)Department of Medical Pharmacology, Faculty of Medicine, Akdeniz University,
Antalya, Turkey.
(4)Department of Medical Biology, School of Medicine, Sanko University, 27090,
Gaziantep, Turkey.
(5)Department of Molecular Medicine, Institute of Graduate Education, Sanko
University, 27090, Gaziantep, Turkey.
(6)Department of Neurology, Derince Training and Research Hospital, Kocaeli,
Turkey.
(7)Instituto de Investigación y Postgrado, Facultad de Ciencias de la Salud,
Universidad Central de Chile, Santiago 8330507, Chile.
Facioscapulohumeral Muscular Dystrophy (FSHD) is in the top three list of all
dystrophies with an approximate 1:8000 incidence. It is not a life-threatening
disease; however, the progression of the disease extends over being wheelchair
bound. Despite some drug trials continuing, including DUX4 inhibition, TGF-ß
inhibition and resokine which promote healthier muscle, there is not an
applicable treatment option for FSHD today. Still, there is a need for new
agents to heal, stop or at least slow down muscle wasting. Current FSHD studies
involving nutraceuticals as vitamin C, vitamin E, coenzyme Q10, zinc, selenium,
and phytochemicals as curcumin or genistein, daidzein flavonoids provide
promising treatment strategies. In this review, we present the clinical and
molecular nature of FSHD and focus on nutraceuticals and phytochemicals that may
alleviate FSHD. In the light of the association of impaired pathophysiological
FSHD pathways with nutraceuticals and phytochemicals according to the
literature, we present both studied and novel approaches that can contribute to
FSHD treatment.
Copyright© Bentham Science Publishers; For any queries, please email at
[email protected].
DOI: 10.2174/1570159X19666210726151924
PMCID: PMC9185762
PMID: 34315378 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21496633
|
1. Handb Clin Neurol. 2011;101:167-80. doi: 10.1016/B978-0-08-045031-5.00013-X.
Facioscapulohumeral dystrophy and scapuloperoneal syndromes.
Orrell RW(1).
Author information:
(1)University Department of Clinical Neurosciences, UCL Institute of Neurology,
London, UK.
Facioscapulohumeral dystrophy (FSHD) is the third most common muscular
dystrophy. It is named for its characteristic involvement of the muscles of the
face and upper arm. It is present worldwide, with a prevalence of around 4 per
100000 and an incidence of about 1 in 20000. Overall lifespan is not affected
significantly. The scapuloperoneal syndrome is a rarer presentation that may
cause some confusion. FSHD is an autosomal dominant condition. The molecular
genetics of FSHD are complex, with current understanding focusing on epigenetic
effects related to contraction-dependent (FSHD1) and contraction-independent
(FSHD2) effects of a hypomethylated repeat sequence (D4Z4), in the presence of a
specific 4qA161 phenotype. Molecular genetic diagnosis is available based on
these findings, but with some complexities which may lead to false-negative
results on routine laboratory investigation. No medication has been demonstrated
to alter the clinical course of the disease significantly. A range of supportive
measures may be applied. This chapter reviews the epidemiology, pathogenesis,
genetics, clinical features, investigation, prognosis, and management of
patients with FSHD and the scapuloperoneal syndrome.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/B978-0-08-045031-5.00013-X
PMID: 21496633 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35567422
|
1. Ann Clin Transl Neurol. 2022 Jun;9(6):810-818. doi: 10.1002/acn3.51560. Epub
2022 May 14.
An expanded access program of risdiplam for patients with Type 1 or 2 spinal
muscular atrophy.
Kwon JM(1), Arya K(2), Kuntz N(3), Phan HC(4), Sieburg C(1), Swoboda KJ(5),
Veerapandiyan A(2), Assman B(6), Bader-Weder S(7), Dickendesher TL(6), Hansen
J(6), Lin H(6), Yan Y(6), Rao VK(3); US Expanded Access Program Working Group.
Author information:
(1)Division of Pediatric Neurology, Department of Neurology, University of
Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
(2)Division of Neurology, Department of Pediatrics, Arkansas Children's
Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas,
USA.
(3)Division of Neurology, Department of Pediatrics, Ann and Robert H. Lurie
Children's Hospital of Chicago, Northwestern University Feinberg School of
Medicine, Chicago, Illinois, USA.
(4)Rare Disease Research, LLC, Atlanta, Georgia, USA.
(5)Department of Neurology, Massachusetts General Hospital, Boston,
Massachusetts, USA.
(6)Genentech, South San Francisco, California, USA.
(7)F. Hoffmann-La Roche Ltd, Basel, Switzerland.
OBJECTIVE: The US risdiplam expanded access program (EAP; NCT04256265) was
opened to provide individuals with Type 1 or 2 spinal muscular atrophy (SMA) who
had no satisfactory treatment options access to risdiplam prior to commercial
availability. The program was designed to collect safety data during risdiplam
treatment.
METHODS: Patients were enrolled from 23 non-preselected sites across 17 states
and treated with risdiplam orally once daily. Eligible patients had a 5q
autosomal recessive Type 1 or 2 SMA diagnosis, were aged ≥2 months at
enrollment, and were ineligible for available and approved SMA treatments or
could not continue treatment due to a medical condition, lack/loss of efficacy,
or the COVID-19 pandemic.
RESULTS: Overall, 155 patients with Type 1 (n = 73; 47.1%) or 2 SMA (n = 82;
52.9%) were enrolled and 149 patients (96.1%) completed the EAP (defined as
obtaining access to commercial risdiplam, if desired). The median treatment
duration was 4.8 months (range, 0.3-9.2 months). The median patient age was
11 years (range, 0-50 years), and most patients (n = 121; 78%) were previously
treated with a disease-modifying therapy. The most frequently reported adverse
events were diarrhea (n = 10; 6.5%), pyrexia (n = 7; 4.5%), and upper
respiratory tract infection (n = 5; 3.2%). The most frequently reported serious
adverse event was pneumonia (n = 3; 1.9%). No deaths were reported.
INTERPRETATION: In the EAP, the safety profile of risdiplam was similar to what
was reported in pivotal risdiplam clinical trials. These safety data provide
further support for the use of risdiplam in the treatment of adult and pediatric
patients with SMA.
© 2022 Genentech Inc. Annals of Clinical and Translational Neurology published
by Wiley Periodicals LLC on behalf of American Neurological Association.
DOI: 10.1002/acn3.51560
PMCID: PMC9186129
PMID: 35567422 [Indexed for MEDLINE]
Conflict of interest statement: JMK was a site principal investigator for the
risdiplam EAP; she is currently the site principal investigator for Novartis
clinical trials for which her institution receives research funding for clinical
trial coordination. She has served on an SMA medical advisory board for Scholar
Rock, Inc. NK serves on medical advisory boards for Astellas, Biogen, Novartis,
Roche, Sarepta, and PTC Therapeutics. KJS has received research grant support
from Biogen. AV has received compensation for ad‐hoc advisory boards/consulting
activity with Biogen, Novartis, AveXis, Sarepta Therapeutics, PTC Therapeutics,
Scholar Rock, and Fibrogen; and research/grant support from Muscular Dystrophy
Association, Parent Project Muscular Dystrophy, Sarepta, Pfizer, Fibrogen,
Genentech, Octapharma, Impax Laboratories, Lilly Pharmaceuticals, and Teva
Pharmaceuticals. VKR has received personal fees from AveXis, Biogen,
Genentech‐Roche, Scholar Rock, PTC Therapeutics, NSPharma, Regenxbio, Sarepta
Therapeutics, France Foundation, Cure SMA, and MDA outside of the submitted
work. BA, SBW, TLD, JH, HL, and YY are employees and shareholders of
Genentech/F. Hoffmann‐La Roche. KA, HCP, and CS have no COIs to disclose.
|
http://www.ncbi.nlm.nih.gov/pubmed/35614235
|
1. Gene Ther. 2023 Feb;30(1-2):8-17. doi: 10.1038/s41434-022-00349-y. Epub 2022
May 26.
Curing SMA: Are we there yet?
Reilly A(#)(1)(2)(3), Chehade L(#)(1)(2)(3), Kothary R(4)(5)(6)(7)(8).
Author information:
(1)Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa,
ON, Canada.
(2)Centre for Neuromuscular Disease, University of Ottawa, Ottawa, ON, Canada.
(3)Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa,
ON, Canada.
(4)Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa,
ON, Canada. [email protected].
(5)Centre for Neuromuscular Disease, University of Ottawa, Ottawa, ON, Canada.
[email protected].
(6)Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa,
ON, Canada. [email protected].
(7)Department of Biochemistry, Microbiology, and Immunology, University of
Ottawa, Ottawa, ON, Canada. [email protected].
(8)Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
[email protected].
(#)Contributed equally
Loss or deletion of survival motor neuron 1 gene (SMN1) is causative for a
severe and devastating neuromuscular disease, Spinal Muscular Atrophy (SMA).
SMN1 produces SMN, a ubiquitously expressed protein, that is essential for the
development and survival of motor neurons. Major advances and developments in
SMA therapeutics are shifting the natural history of the disease. With three
relatively new available therapies, nusinersen (Spinraza), onasemnogene
abeparvovec (Zolgensma), and risdiplam (Evrysdi), patients survive longer and
have improved outcomes. However, patients and families continue to face many
challenges associated with use of these therapies, including poor treatment
response and a variability in the benefits to those that do respond, suggesting
that the quest for the SMA cure is not over. In this review, we discuss the
current therapies, their limitations, and highlight necessary gaps that need to
be addressed to guarantee the best outcomes for SMA patients.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41434-022-00349-y
PMID: 35614235 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34620695
|
1. Drug Metab Dispos. 2022 Jan;50(1):65-75. doi: 10.1124/dmd.121.000563. Epub
2021 Oct 7.
Addressing Today's Absorption, Distribution, Metabolism, and Excretion (ADME)
Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case
Study of the SMN2 mRNA Splicing Modifier Risdiplam.
Fowler S(1), Brink A(1), Cleary Y(1), Günther A(1), Heinig K(1), Husser C(1),
Kletzl H(1), Kratochwil N(1), Mueller L(1), Savage M(1), Stillhart C(1), Tuerck
D(1), Ullah M(1), Umehara K(1), Poirier A(2).
Author information:
(1)Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche
Innovation Center Basel (S.F., A.B., Y.C., A.G., K.H., C.H., H.K, N.K., L.M.,
D.T., M.U., K.U., A.P.) and Formulation & Process Sciences, Pharmaceutical
Research and Development (C.S.), F. Hoffmann-La Roche Ltd., Basel, Switzerland;
and Unilabs York Bioanalytical Solutions, Sandwich, United Kingdom (M.S.).
(2)Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche
Innovation Center Basel (S.F., A.B., Y.C., A.G., K.H., C.H., H.K, N.K., L.M.,
D.T., M.U., K.U., A.P.) and Formulation & Process Sciences, Pharmaceutical
Research and Development (C.S.), F. Hoffmann-La Roche Ltd., Basel, Switzerland;
and Unilabs York Bioanalytical Solutions, Sandwich, United Kingdom (M.S.)
[email protected].
Small molecules that present complex absorption, distribution, metabolism, and
elimination (ADME) properties can be challenging to investigate as potential
therapeutics. Acquiring data through standard methods can yield results that are
insufficient to describe the in vivo situation, which can affect downstream
development decisions. Implementing in vitro-in vivo-in silico strategies
throughout the drug development process is effective in identifying and
mitigating risks while speeding up their development. Risdiplam (Evrysdi)-an
orally bioavailable, small molecule approved by the US Food and Drug
Administration and more recently by the European Medicines Agency for the
treatment of patients ≥2 months of age with spinal muscular atrophy-is presented
here as a case study. Risdiplam is a low-turnover compound whose metabolism is
mediated through a non-cytochrome P450 enzymatic pathway. Four main challenges
of risdiplam are discussed: predicting in vivo hepatic clearance, determining in
vitro metabolites with regard to metabolites in safety testing guidelines,
elucidating enzymes responsible for clearance, and estimating potential
drug-drug interactions. A combination of in vitro and in vivo results was
successfully extrapolated and used to develop a robust physiologically based
pharmacokinetic model of risdiplam. These results were verified through early
clinical studies, further strengthening the understanding of the ADME properties
of risdiplam in humans. These approaches can be applied to other compounds with
similar ADME profiles, which may be difficult to investigate using standard
methods. SIGNIFICANCE STATEMENT: Risdiplam is the first approved,
small-molecule, survival of motor neuron 2 mRNA splicing modifier for the
treatment of spinal muscular atrophy. The approach taken to characterize the
absorption, distribution, metabolism, and excretion (ADME) properties of
risdiplam during clinical development incorporated in vitro-in vivo-in silico
techniques, which may be applicable to other small molecules with challenging
ADME. These strategies may be useful in improving the speed at which future drug
molecules can be developed.
Copyright © 2021 by The Author(s).
DOI: 10.1124/dmd.121.000563
PMID: 34620695 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36376097
|
1. Neurol Neuroimmunol Neuroinflamm. 2022 Nov 14;10(1):e200052. doi:
10.1212/NXI.0000000000200052. Print 2023 Jan.
Serum GFAP and NfL Levels Differentiate Subsequent Progression and Disease
Activity in Patients With Progressive Multiple Sclerosis.
Barro C(1), Healy BC(1), Liu Y(1), Saxena S(1), Paul A(1), Polgar-Turcsanyi
M(1), Guttmann CRG(1), Bakshi R(1), Kropshofer H(1), Weiner HL(1), Chitnis T(2).
Author information:
(1)From the Harvard Medical School (C.B., B.C.H., M.P.-T., C.R.G.G., R.B.,
H.L.W., T.C.); Ann Romney Center for Neurologic Diseases (C.B., B.C.H., Y.L.,
S.S., A.P., M.P.-T., C.R.G.G., R.B., H.L.W., T.C.), Brigham and Women's
Hospital; Brigham Multiple Sclerosis Center (R.B., H.L.W., T.C.), Department of
Neurology, Brigham and Women's Hospital; Center for Neurological Imaging
(C.R.G.G.), Department of Radiology, Brigham and Women's Hospital; Biostatistics
Center (B.C.H.), Massachusetts General Hospital, Boston, MA; and Novartis Pharma
AG (H.K.), Basel, Switzerland.
(2)From the Harvard Medical School (C.B., B.C.H., M.P.-T., C.R.G.G., R.B.,
H.L.W., T.C.); Ann Romney Center for Neurologic Diseases (C.B., B.C.H., Y.L.,
S.S., A.P., M.P.-T., C.R.G.G., R.B., H.L.W., T.C.), Brigham and Women's
Hospital; Brigham Multiple Sclerosis Center (R.B., H.L.W., T.C.), Department of
Neurology, Brigham and Women's Hospital; Center for Neurological Imaging
(C.R.G.G.), Department of Radiology, Brigham and Women's Hospital; Biostatistics
Center (B.C.H.), Massachusetts General Hospital, Boston, MA; and Novartis Pharma
AG (H.K.), Basel, Switzerland. [email protected].
BACKGROUND AND OBJECTIVES: Neurodegeneration and astrocytic activation are
pathologic hallmarks of progressive multiple sclerosis (MS) and can be
quantified by serum neurofilament light chain (sNfL) and glial fibrillary acidic
protein (sGFAP). We investigated sNfL and sGFAP as tools for stratifying
patients with progressive MS based on progression and disease activity status.
METHODS: We leveraged our Comprehensive Longitudinal Investigation of MS at the
Brigham and Women's Hospital (CLIMB) natural history study, which includes
clinical, MRI data and serum samples collected over more than 20 years. We
included patients with MS with a confirmed Expanded Disability Status Scale
(EDSS) score ≥3 that corresponds with our classifier for patients at high risk
of underlying progressive pathology. We analyzed sNfL and sGFAP within 6 months
from the confirmed EDSS score ≥3 corresponding with our baseline visit. Patients
who further developed 6-month confirmed disability progression (6mCDP) were
classified as progressors. We further stratified our patients into
active/nonactive based on new brain/spinal cord lesions or relapses in the 2
years before baseline or during follow-up. Statistical analysis on
log-transformed sGFAP/sNfL assessed the baseline association with demographic,
clinical, and MRI features and associations with future disability.
RESULTS: We included 257 patients with MS who had an average EDSS score of 4.0
and a median follow-up after baseline of 7.6 years. sNfL was higher in patients
with disease activity in the 2 years before baseline (adjusted β = 1.21; 95% CI
1.04-1.42; p = 0.016), during the first 2 years of follow-up (adjusted β = 1.17;
95% CI = 1.01-1.36; p = 0.042). sGFAP was not increased in the presence of
disease activity. Higher sGFAP levels, but not sNfL levels, were associated with
higher risk of 6mCDP (adjusted hazard ratio [HR] = 1.71; 95% CI = 1.19-2.45; p =
0.004). The association was stronger in patients with low sNfL (adjusted HR =
2.44; 95% CI 1.32-4.52; p = 0.005) and patients who were nonactive in the 2
years prior or after the sample.
DISCUSSION: Higher levels of sGFAP correlated with subsequent progression,
particularly in nonactive patients, whereas sNfL reflected acute disease
activity in patients with MS at high risk of underlying progressive pathology.
Thus, sGFAP and sNfL levels may be used to stratify patients with progressive MS
for clinical research studies and clinical trials and may inform clinical care.
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on
behalf of the American Academy of Neurology.
DOI: 10.1212/NXI.0000000000200052
PMCID: PMC9749933
PMID: 36376097 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34274959
|
1. Pediatr Res. 2022 Jun;91(7):1735-1740. doi: 10.1038/s41390-021-01649-6. Epub
2021 Jul 17.
Associations between neurofilament light-chain protein, brain structure, and
chronic kidney disease.
van der Plas E(1), Lullmann O(1), Hopkins L(1), Schultz JL(1)(2), Nopoulos
PC(1), Harshman LA(3).
Author information:
(1)Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa
City, IA, USA.
(2)University of Iowa College of Pharmacy, Iowa City, IA, USA.
(3)University of Iowa Stead Family Department of Pediatrics, Iowa City, IA, USA.
[email protected].
BACKGROUND: Neurofilament light-chain (NfL) protein is a blood-based marker of
neuroaxonal injury. We sought to (1) compare plasma NfL levels in children with
chronic kidney disease (CKD) and healthy peers, (2) characterize the
relationship between NfL level and kidney function, and (3) evaluate NfL as a
predictor of abnormal brain structure in CKD.
METHODS: Sixteen children with CKD due to congenital kidney anomalies and 23
typically developing peers were included. Plasma NfL was quantified using
single-molecule array immunoassay. Participants underwent structural magnetic
resonance imaging. Multiple linear regression models were used to evaluate the
association between plasma NfL levels, kidney function, and brain structure.
RESULTS: An age × group interaction was identified whereby NfL levels increased
with age in the CKD group only (estimate = 0.65; confidence interval
(CI) = 0.08-1.22; p = 0.026). Decreased kidney function was associated with
higher NfL levels (estimate = -0.10; CI = -0.16 to -0.04; p = 0.003). Lower
cerebellar gray matter volume predicted increased plasma NfL levels
(estimate = -0.00024; CI = -0.00039 to 0.00009; p = 0.004) within the CKD group.
CONCLUSIONS: Children with CKD show accelerated age-related increases in NfL
levels. NfL level is associated with lower kidney function and abnormal brain
structure in CKD.
IMPACT: NfL is a component of the neuronal cytoskeleton providing structural
axonal support. Elevated NfL has been described in relation to gray and white
matter brain volume loss. We have previously described the abnormal cerebellar
gray matter in CKD. We explored the relationship between NfL, CKD, and brain
volume. There is an accelerated, age-related increase in NfL level in CKD.
Within the CKD sample, NfL level is associated with abnormal kidney function and
brain structure. Decreased kidney function may be linked to abnormal neuronal
integrity in pediatric CKD.
© 2021. The Author(s), under exclusive licence to the International Pediatric
Research Foundation, Inc.
DOI: 10.1038/s41390-021-01649-6
PMCID: PMC8761779
PMID: 34274959 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure statement: There are no financial
relationships to disclose or conflict of interest for the authorship team.
|
http://www.ncbi.nlm.nih.gov/pubmed/34212756
|
1. Mult Scler. 2022 Apr;28(4):512-521. doi: 10.1177/13524585211024978. Epub 2021
Jul 2.
Longitudinal follow-up of serum biomarkers in patients with neuromyelitis optica
spectrum disorder.
Kim H(1), Lee EJ(2), Kim S(3), Choi LK(4), Kim HJ(3), Kim HW(5), Chung K(5), Seo
D(5), Moon S(5), Kim KK(5), Lim YM(5).
Author information:
(1)Department of Neurology, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, South Korea Graduate School of Medical Science and Engineering,
Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
(2)Department of Neurology, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, South Korea Department of Convergence Medicine, Asan Medical
Institute of Convergence Science and Technology, Seoul, South Korea.
(3)Department of Convergence Medicine, Asan Medical Institute of Convergence
Science and Technology, Seoul, South Korea.
(4)Graduate School of Medical Science and Engineering, Korea Advanced Institute
of Science and Technology, Daejeon, South Korea.
(5)Department of Neurology, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, South Korea.
BACKGROUND: Recently, several serum biomarkers have been proposed in
Neuromyelitis Optica Spectrum Disorders (NMOSD) to monitor disease activity.
OBJECTIVE: The objective of the study is to evaluate the longitudinal clinical
value of serum biomarkers in patients with NMOSD.
METHODS: We prospectively recruited consecutive NMOSD patients with
anti-aquaporin-4 antibody and obtained serum samples at enrollment, after
6-12 months of follow-up (main period), and at attacks. Using single-molecule
array assays, we evaluated longitudinal changes of serum neurofilament light
chain (NfL), glial fibrillary acidic protein (GFAP), and GFAP/NfL levels.
RESULTS: Overall, 64 patients (58 women) were enrolled (age: 51 years, disease
duration: 6.7 years) and 133 samples were obtained. Among patients who did not
develop new attacks during the main period (n = 62), serum levels of NfL, GFAP,
and GFAP/NfL were significantly decreased over time in patients with attacks
(<2 months) at enrollment (n = 14 (23%)), whereas serum NfL and GFAP levels
gradually increased in the others (n = 48 (77%)). During the study, five (8%)
patients developed new attacks; only serum GFAP levels increased consistently
upon these events compared with baseline levels. To differentiate attacks from
remissions, serum GFAP levels showed the largest area under the receiver
operating characteristic curve (0.876, 95% confidence interval: 0.801-0.951).
CONCLUSION: Among NfL, GFAP, and GFAP/NfL, serum GFAP might be the most
appropriate for monitoring NMOSD longitudinally, which warrants future
confirming studies.
DOI: 10.1177/13524585211024978
PMID: 34212756 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36280258
|
1. Neurol Neuroimmunol Neuroinflamm. 2022 Oct 24;10(1):e200044. doi:
10.1212/NXI.0000000000200044. Print 2023 Jan.
Neurofilament Light Chain Levels Are Predictive of Clinical Conversion in
Radiologically Isolated Syndrome.
Rival M(1), Thouvenot E(2), Du Trieu de Terdonck L(1), Laurent-Chabalier S(1),
Demattei C(1), Uygunoglu U(1), Castelnovo G(1), Cohen M(1), Okuda DT(1),
Kantarci OH(1), Pelletier D(1), Azevedo C(1), Marin P(1), Lehmann S(1), Siva
A(1), Mura T(1), Lebrun-Frenay C(1); SFSEP and RISC.
Author information:
(1)From the Department of Neurology (M.R., E.T., G.C.), Nîmes University
Hospital Center, Univ. Montpellier; Functional Genomics Institute (M.R., E.T.,
L.D.T.T., P.M.), Univ. Montpellier, CNRS, INSERM; Department of Biostatistics
(S.L.-C., C.D., T.M.), Clinical Epidemiology, Public Health and Innovation in
Methdology (BESPIM), Nîmes University Hospital Center, Univ. Montpellier,
France; Department of Neurology (U.U., A.S.), Cerrahpasa School of Medecine,
University of Istanbul, Turkey; Centre de Ressources et Compétences Sclérose En
Plaques (CRCSEP) (M.C., C.L.-F.), CHU de Nice, Hôpital Pasteur 2, Université
Côte d'Azur, UR2CA-URRIS, France; UT Southwestern Medical Center (D.T.O.),
Dallas, TX; Mayo Clinic (O.H.K.), Rochester, MN; University of South California
(D.P., C.A.), Los Angeles; and LBPC-PPC (S.L.), Univ. Montpellier, CHU
Montpellier, INM, INSERM, France.
(2)From the Department of Neurology (M.R., E.T., G.C.), Nîmes University
Hospital Center, Univ. Montpellier; Functional Genomics Institute (M.R., E.T.,
L.D.T.T., P.M.), Univ. Montpellier, CNRS, INSERM; Department of Biostatistics
(S.L.-C., C.D., T.M.), Clinical Epidemiology, Public Health and Innovation in
Methdology (BESPIM), Nîmes University Hospital Center, Univ. Montpellier,
France; Department of Neurology (U.U., A.S.), Cerrahpasa School of Medecine,
University of Istanbul, Turkey; Centre de Ressources et Compétences Sclérose En
Plaques (CRCSEP) (M.C., C.L.-F.), CHU de Nice, Hôpital Pasteur 2, Université
Côte d'Azur, UR2CA-URRIS, France; UT Southwestern Medical Center (D.T.O.),
Dallas, TX; Mayo Clinic (O.H.K.), Rochester, MN; University of South California
(D.P., C.A.), Los Angeles; and LBPC-PPC (S.L.), Univ. Montpellier, CHU
Montpellier, INM, INSERM, France. [email protected].
BACKGROUND AND OBJECTIVES: To evaluate the predictive value of serum
neurofilament light chain (sNfL) and CSF NfL (cNfL) in patients with
radiologically isolated syndrome (RIS) for evidence of disease activity (EDA)
and clinical conversion (CC).
METHODS: sNfL and cNfL were measured at RIS diagnosis by single-molecule array
(Simoa). The risk of EDA and CC according to sNfL and cNfL was evaluated using
the Kaplan-Meier analysis and multivariate Cox regression models including age,
spinal cord (SC) or infratentorial lesions, oligoclonal bands, CSF chitinase
3-like protein 1, and CSF white blood cells.
RESULTS: Sixty-one patients with RIS were included. At diagnosis, sNfL and cNfL
were correlated (Spearman r = 0.78, p < 0.001). During follow-up, 47 patients
with RIS showed EDA and 36 patients showed CC (median time 12.6 months, 1-86).
When compared with low levels, medium and high cNfL (>260 pg/mL) and sNfL (>5.0
pg/mL) levels were predictive of EDA (log rank, p < 0.01 and p = 0.02,
respectively). Medium-high cNfL levels were predictive of CC (log rank, p <
0.01). In Cox regression models, cNfL and sNfL were independent factors of EDA,
while SC lesions, cNfL, and sNfL were independent factors of CC.
DISCUSSION: cNfL >260 pg/mL and sNfL >5.0 pg/mL at diagnosis are independent
predictive factors of EDA and CC in RIS. Although cNfL predicts disease activity
better, sNfL is more accessible than cNfL and can be considered when a lumbar
puncture is not performed.
CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people
with radiologic isolated syndrome (RIS), initial serum and CSF NfL levels are
associated with subsequent evidence of disease activity or clinical conversion.
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on
behalf of the American Academy of Neurology.
DOI: 10.1212/NXI.0000000000200044
PMCID: PMC9621336
PMID: 36280258 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34283286
|
1. J Neurol. 2022 Feb;269(2):815-823. doi: 10.1007/s00415-021-10660-0. Epub 2021
Jul 20.
Serum neurofilament light chain or glial fibrillary acidic protein in the
diagnosis and prognosis of brain metastases.
Lin X(#)(1), Lu T(#)(2), Deng H(#)(1), Liu C(2), Yang Y(1), Chen T(1), Qin Y(1),
Xie X(1), Xie Z(1), Liu M(1), Ouyang M(1), Li S(1), Song Y(3), Zhong N(1), Qiu
W(4), Zhou C(5).
Author information:
(1)State Key Laboratory of Respiratory Disease, National Clinical Research
Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First
Affiliated Hospital, Guangzhou Medical University, 151# Yanjiang Road,
Guangzhou, 510120, China.
(2)Department of Neurology, Psychological and Neurological Diseases Research
Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou,
510630, China.
(3)Department of Respiratory and Critical Care Medicine, Jinling Hospital,
Nanjing, China.
(4)Department of Neurology, Psychological and Neurological Diseases Research
Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou,
510630, China. [email protected].
(5)State Key Laboratory of Respiratory Disease, National Clinical Research
Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First
Affiliated Hospital, Guangzhou Medical University, 151# Yanjiang Road,
Guangzhou, 510120, China. [email protected].
(#)Contributed equally
INTRODUCTION: Brain metastases (BM) remains the most cumbersome disease burden
in patients with lung cancer. This study aimed to investigate whether serum
brain injury biomarkers can indicate BM, to further establish related diagnostic
models, or to predict prognosis of BM.
MATERIALS AND METHODS: This was a prospective study of patients diagnosed with
lung cancer with BM (BM group), with lung cancer without BM (NBM group), and
healthy participants (control group). Serum neurofilament light chain (NfL) and
glial fibrillary acidic protein (GFAP) were detected at baseline. We identified
and integrated the risk factors of BM to establish diagnostic models.
RESULTS: A total of 158 patients were included (n = 37, 57, and 64 in the BM,
NBM, and control groups, respectively). Serum biomarker levels were
significantly higher in the NBM group than in the control group. Higher serum
NfL and GFAP concentrations were associated with BM (odds ratios, 3.06 and 1.79,
respectively). NfL (area under curve [AUC] = 0.77, p < 0.001) and GFAP
(AUC = 0.64, p = 0.02) had diagnostic value for BM. The final diagnostic model
included NfL level, age, Karnofsky Performance Status. The model had an AUC
value of 0.83 (95% confidence interval [CI] 0.75-0.92). High NfL concentration
was correlated with poor overall survival of patients with BM (hazard ratio,
3.31; 95% CI 1.22-9.04; p = 0.019).
CONCLUSION: Serum NfL and GFAP could be potential diagnostic biomarkers for BM
in patients with lung cancer. We established a model that can provide individual
diagnoses of BM. Higher NfL level may be associated with poor prognosis of
patients with BM.
© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.
DOI: 10.1007/s00415-021-10660-0
PMID: 34283286 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34313819
|
1. J Neurol. 2022 Mar;269(3):1522-1529. doi: 10.1007/s00415-021-10714-3. Epub
2021 Jul 27.
Comparative diagnosis interest of NfL and pNfH in CSF and plasma in a context of
FTD-ALS spectrum.
Escal J(1)(2), Fourier A(3)(4), Formaglio M(5)(6), Zimmer L(2), Bernard E(7)(8),
Mollion H(5)(6), Bost M(1), Herrmann M(9), Ollagnon-Roman E(10), Quadrio
I(#)(1)(2)(6), Dorey JM(#)(9)(11).
Author information:
(1)Laboratory of Neurobiology and Neurogenetics, Department of Biochemistry and
Molecular Biology, Lyon University Hospital, Bron, France.
(2)BIORAN Team, Lyon Neuroscience Research Center, CNRS UMR 5292, INSERM U1028,
Lyon 1 University, Bron, France.
(3)Laboratory of Neurobiology and Neurogenetics, Department of Biochemistry and
Molecular Biology, Lyon University Hospital, Bron, France.
[email protected].
(4)BIORAN Team, Lyon Neuroscience Research Center, CNRS UMR 5292, INSERM U1028,
Lyon 1 University, Bron, France. [email protected].
(5)Neurocognition and Neuro-Ophthalmology Department, Lyon University Hospital,
Bron, France.
(6)Center for Memory Resources and Research, Lyon University Hospital, Lyon 1
University, Villeurbanne, France.
(7)Reference Center of ALS of Lyon, Lyon University Hospital, Lyon 1 University,
Bron, France.
(8)NeuroMyoGène Institute, CNRS UMR 5310, INSERM U1217, Lyon 1 University, Lyon,
France.
(9)Department of Aging Psychiatry, Hospital Le Vinatier, Bron, France.
(10)Department of Predictive Medicine of Neurological and Neurodegenerative
Diseases, Lyon University Hospital, Lyon, France.
(11)Brain Dynamics and Cognition Team, Lyon Neuroscience Research Center, CNRS
UMR 5292, INSERM U1028, Lyon, France.
(#)Contributed equally
OBJECTIVE: The 'Frontotemporal dementia-Amyotrophic lateral sclerosis Spectrum'
(FAS) encompasses different phenotypes, including cognitive disorders
(frontotemporal dementia, FTD) and/or motor impairments (amyotrophic lateral
sclerosis, ALS). The aim of this study was to apprehend the specific uses of
neurofilaments light chain (NfL) and phosphorylated neurofilaments heavy chain
(pNfH) in a context of FAS.
METHODS: First, NfL and pNfH were measured in 39 paired cerebrospinal fluid
(CSF) and plasma samples of FAS and primary psychiatric disorders (PPD)
patients, considered as controls. Secondly, additional plasma samples were
included to examine a larger cohort of 81 samples composed of symptomatic FAS
and PPD patients, presymptomatic and non-carrier relatives individuals. The
measures were performed using Simoa technology.
RESULTS: There was a positive correlation between CSF and plasma values for NfL
(p < 0.0001) and for pNfH (p = 0.0036). NfL values were higher for all
phenotypes of symptomatic FAS patients compared to PPD patients (p = 0.0016 in
CSF; p = 0.0003 in plasma). On the contrary, pNfH values were solely increased
in FAS patients exhibiting motor impairment. Unlike symptomatic FAS patients,
presymptomatic cases had comparable concentrations with non-carrier individuals.
CONCLUSION: NfL, but not pNfH, appeared to be useful in a context of
differential diagnosis between FTD and psychiatric patients. Nevertheless, pNfH
seem more specific for the diagnosis and follow-up of motor impairments. In each
specific indication, measures in CSF and plasma will provide identical
interpretations.
© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.
DOI: 10.1007/s00415-021-10714-3
PMID: 34313819 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33893614
|
1. Cerebellum. 2022 Feb;21(1):39-47. doi: 10.1007/s12311-021-01257-4. Epub 2021
Apr 24.
Neurofilament Light Chain Is a Biomarker of Neurodegeneration in Ataxia
Telangiectasia.
Donath H(1), Woelke S(2), Schubert R(2), Kieslich M(3), Theis M(3), Auburger
G(4), Duecker RP(2), Zielen S(2).
Author information:
(1)Division of Allergology, Pulmonology and Cystic Fibrosis, Department for
Children and Adolescents, Goethe University, Frankfurt, Germany.
[email protected].
(2)Division of Allergology, Pulmonology and Cystic Fibrosis, Department for
Children and Adolescents, Goethe University, Frankfurt, Germany.
(3)Division of Pediatric Neurology, Department for Children and Adolescents,
Goethe University, Frankfurt, Germany.
(4)Experimental Neurology, Medical School, Goethe University, Frankfurt,
Germany.
Erratum in
Cerebellum. 2022 Feb;21(1):48. doi: 10.1007/s12311-021-01280-5.
Ataxia telangiectasia (A-T) is a progressive and life-limiting disease
associated with cerebellar ataxia due to progressive cerebellar degeneration. In
addition to ataxia, which is described in detail, the presence of chorea,
dystonia, oculomotor apraxia, athetosis, parkinsonism, and myoclonia are typical
manifestations of the disease. The study aimed to evaluate the specificity and
sensitivity of neurofilament light chain (NfL) as a biomarker of
neurodegeneration in relation to SARA score. In this prospective trial, one
visit of 42 A-T patients aged 1.3-25.6 years (mean 11.6 ± 7.3 years) was
performed, in which NfL was determined from serum by ELISA. Additionally, a
neurological examination of the patients was performed. Blood was collected from
19 healthy volunteers ≥ 12 years of age. We found significantly increased levels
of NfL in patients with A-T compared to healthy controls (21.5 ± 3.6 pg/mL vs.
9.3 ± 0.49 pg/mL, p ≤ 0.01). There was a significant correlation of NfL with
age, AFP, and SARA. NfL is a new potential progression biomarker in blood for
neurodegeneration in A-T which increases with age.
© 2021. The Author(s).
DOI: 10.1007/s12311-021-01257-4
PMCID: PMC8885493
PMID: 33893614 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
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http://www.ncbi.nlm.nih.gov/pubmed/33759425
|
1. Clin Chem Lab Med. 2021 Mar 23;60(4):569-575. doi: 10.1515/cclm-2020-1276.
Print 2022 Mar 28.
Biological variation of serum neurofilament light chain.
Hviid CVB(1)(2), Madsen AT(3), Winther-Larsen A(1).
Author information:
(1)Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus,
Denmark.
(2)Department of Clinical Biochemistry, Horsens Regional Hospital, Horsens,
Denmark.
(3)Department of Microbiology and Immunology, Albert Einstein College of
Medicine, New York, NY, USA.
OBJECTIVES: The neurofilament light chain (NfL) has emerged as a versatile
biomarker for CNS-diseases and is approaching clinical use. The observed changes
in NfL levels are frequently of limited magnitude and in order to make clinical
decisions based on NfL measurements, it is essential that biological variation
is not confused with clinically relevant changes. The present study was designed
to evaluate the biological variation of serum NfL.
METHODS: Apparently healthy individuals (n=33) were submitted to blood draws for
three days in a row. On the second day, blood draws were performed every third
hour for 12 h. NfL was quantified in serum using the Simoa™ HD-1 platform. The
within-subject variation (CVI) and between-subject variation (CVG) were
calculated using linear mixed-effects models.
RESULTS: The overall median value of NfL was 6.3 pg/mL (range 2.1-19.1). The CVI
was 3.1% and the CVG was 35.6%. An increase in two serial measurements had to
exceed 24.3% to be classified as significant at the 95% confidence level. Serum
NfL levels remained stable during the day (p=0.40), whereas a minute variation
(6.0-6.6 pg/mL) was observed from day-to-day (p=0.02).
CONCLUSIONS: Serum NfL is subject to tight homeostatic regulation with none or
neglectable semidiurnal and day-to-day variation, but considerable
between-subject variation exists. This emphasizes serum NfL as a well-suited
biomarker for disease monitoring, but warrants caution when interpreting NfL
levels in relation to reference intervals in a diagnosis setting. Furthermore,
NfL's tight regulation requires that the analytical variation is kept at a
minimum.
© 2021 Walter de Gruyter GmbH, Berlin/Boston.
DOI: 10.1515/cclm-2020-1276
PMID: 33759425 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35658739
|
1. Mult Scler. 2022 Oct;28(12):1859-1870. doi: 10.1177/13524585221097296. Epub
2022 Jun 4.
Serum neurofilament light chain concentration predicts disease worsening in
multiple sclerosis.
Brune S(1), Høgestøl EA(2), de Rodez Benavent SA(3), Berg-Hansen P(4), Beyer
MK(5), Leikfoss IS(6), Bos SD(7), Sowa P(8), Brunborg C(9), Andorra M(10),
Pulido Valdeolivas I(10), Asseyer S(11), Brandt A(12), Chien C(12), Scheel
M(13), Blennow K(14), Zetterberg H(15), Kerlero de Rosbo N(16), Paul F(12),
Uccelli A(17), Villoslada P(10), Berge T(18), Harbo HF(7).
Author information:
(1)Institute of clinical Medicine, University of Oslo, Oslo, Norway/Department
of Neurology, Oslo University Hospital, University of Oslo, Oslo, Norway.
(2)Institute of Clinical Medicine, University of Oslo, Oslo, Norway/Department
of Neurology, Oslo University Hospital, Oslo, Norway; Department of Psychology,
University of Oslo, Oslo, Norway.
(3)Department of Ophthalmology, Oslo University Hospital, Oslo, Norway.
(4)Department of Neurology, Oslo University Hospital, Oslo, Norway.
(5)Institute of Clinical Medicine, University of Oslo, Oslo, Norway/Division of
Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
(6)Department of Neurology, Oslo University Hospital, Oslo, Norway/Department of
Research, Innovation and Education, Oslo University Hospital, Oslo, Norway.
(7)Institute of Clinical Medicine, University of Oslo, Oslo, Norway/Department
of Neurology, Oslo University Hospital, Oslo, Norway.
(8)Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo,
Norway.
(9)Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital,
Oslo, Norway.
(10)Institut d'Investigacions Biomediques August Pi Sunyer, Barcelona, Spain.
(11)Experimental and Clinical Research Center, Max Delbrueck Center for
Molecular Medicine and Charité-Universitaetsmedizin Berlin, Berlin, Germany.
(12)Experimental and Clinical Research Center, Max Delbrueck Center for
Molecular Medicine and Charité-Universitaetsmedizin Berlin, Berlin,
Germany/NeuroCure Clinical Research Center, Charité-Universitaetsmedizin Berlin,
corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin,
and Berlin Institute of Health, Berlin, Germany.
(13)NeuroCure Clinical Research Center, Charité-Universitaetsmedizin Berlin,
corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin,
and Berlin Institute of Health, Berlin, Germany/Department of Neuroradiology,
Charité-Universitaetsmedizin Berlin, corporate member of Freie Universität
Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin,
Germany.
(14)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital,
Mölndal, Sweden.
(15)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital,
Mölndal, Sweden/Department of Psychiatry and Neurochemistry, Institute of
Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg,
Mölndal, Sweden/Department of Neurodegenerative Disease, Institute of Neurology,
University College London, London, UK/UK Dementia Research Institute at UCL,
London, UK/Hong Kong Center for Neurodegenerative Diseases, Shatin, Hong Kong,
China.
(16)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics,
Maternal and Child Health, University of Genoa, Genoa, Italy.
(17)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics,
Maternal and Child Health, University of Genoa, Genoa, Italy/Center of
Excellence for Biomedical Research, University of Genoa, Genoa, Italy/IRCCS
Ospedale Policlinico San Martino, Genoa, Italy.
(18)Department of Research, Innovation and Education, Oslo University Hospital,
Oslo, Norway/Department of Mechanical, Electronic and Chemical Engineering, Oslo
Metropolitan University, Oslo, Norway.
BACKGROUND: Serum neurofilament light (sNfL) chain is a promising biomarker
reflecting neuro-axonal injury in multiple sclerosis (MS). However, the ability
of sNfL to predict outcomes in real-world MS cohorts requires further
validation.
OBJECTIVE: The aim of the study is to investigate the associations of sNfL
concentration, magnetic resonance imaging (MRI) and retinal optical coherence
tomography (OCT) markers with disease worsening in a longitudinal European
multicentre MS cohort.
METHODS: MS patients (n = 309) were prospectively enrolled at four centres and
re-examined after 2 years (n = 226). NfL concentration was measured by single
molecule array assay in serum. The patients' phenotypes were thoroughly
characterized with clinical examination, retinal OCT and MRI brain scans. The
primary outcome was disease worsening at median 2-year follow-up.
RESULTS: Patients with high sNfL concentrations (⩾8 pg/mL) at baseline had
increased risk of disease worsening at median 2-year follow-up (odds ratio (95%
confidence interval) = 2.8 (1.5-5.3), p = 0.001). We found no significant
associations of MRI or OCT measures at baseline with risk of disease worsening.
CONCLUSION: Serum NfL concentration was the only factor associated with disease
worsening, indicating that sNfL is a useful biomarker in MS that might be
relevant in a clinical setting.
DOI: 10.1177/13524585221097296
PMCID: PMC9493412
PMID: 35658739 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Conflicting Interests: The
author(s) declared the following potential conflicts of interest with respect to
the research, authorship and/or publication of this article: S.B. has received
honoraria for lecturing from Biogen and Novartis. E.A.H. received honoraria for
lecturing and advisory board activity from Biogen, Merck and Sanofi Genzyme and
unrestricted research grant from Merck. S.A.d.R.B. has received honoraria for
lecturing from Teva and an unrestricted grant from Odd Fellows. P.B.-H. has
received advisory board and/or speaker honoraria from Novartis, UCB, Sanofi,
Merck and Biogen Idec. M.K.B. has received honoraria for lecturing from Novartis
and Biogen Idec and served on the advisory board for Biogen. I.S.L. has received
unrestricted research grants from Biogen. S.D.B. reports no disclosures. P.S.
has received honoraria for lecturing and travel support from Merck. C.B. reports
no disclosures. M.A. is currently an employee of Roche, all the work in this
paper is based on his previous work at IDIBAPS. He holds stock from Bionure
Farma SL, Attune Neurosciences, Inc. and Goodgut SL. I.P.V. has received travel
reimbursement from Roche Spain, Novartis and Genzyme-Sanofi, and she is founder
and holds stock in Aura Robotics SL. She is employee at UCB Pharma since July
2020 and all the work in this paper is based on her previous work at IDIBAPS.
S.A. received a conference grant from Celgene and honoraria for lecturing from
Alexion, Bayer and Roche. A.B. is cofounder and shareholder of Nocturne GmbH and
Motognosis GmbH. He is named as inventor on several patent applications and
patents describing multiple sclerosis serum biomarkers, motion analysis and
retinal image analysis. C.C. has received honoraria for lecturing from Bayer and
research grants from Novartis. M.S. has received funding unrelated to this work
from German Research Foundation, Federal Ministry of Education and Research and
Federal Ministry for Economic Affairs and Energy. He is holding patents for 3D
printing of computed tomography models and is shareholder of PhantomX GmbH. K.B.
has served as a consultant, at advisory boards, or at data monitoring committees
for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu,
Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of
Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU
Ventures Incubator Program. H.Z. has served at scientific advisory boards for
Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon
Therapeutics, Nervgen, AZTherapies and CogRx; has given lectures in symposia
sponsored by Cellectricon, Fujirebio, Alzecure and Biogen; and is a co-founder
of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU
Ventures Incubator Program. N.K.d.R. reports no disclosures. F.P. received
honoraria and research support from Alexion, Bayer and Biogen. A.U. has received
personal compensation from Novartis, Biogen, Merck, Roche and Sanofi Genzyme for
public speaking and advisory boards. A.U. received funding for research by
Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health and Banco
San Paolo. P.V. received consultancy fees and holds stocks from Accure
Therapeutics SL, Spiral Therapeutics Inc., Clight Inc., Neuroprex Inc., QMenta
Inc. and Attune Neurosciences Inc. T.B. has received unrestricted research
grants from Biogen and Sanofi Genzyme. H.F.H. has received honoraria for
lecturing or advice from Biogen Merck, Roche, Novartis and Sanofi.
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http://www.ncbi.nlm.nih.gov/pubmed/35582775
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1. Br J Haematol. 2022 Aug;198(4):721-728. doi: 10.1111/bjh.18247. Epub 2022 May
17.
Screening for neurodegeneration in Langerhans cell histiocytosis with
neurofilament light in plasma.
Sveijer M(1)(2), von Bahr Greenwood T(1)(3), Jädersten M(4)(5), Kvedaraite
E(1)(6)(7), Zetterberg H(8)(9)(10)(11)(12), Blennow K(8)(9), Lourda M(1)(6),
Gavhed D(1)(3), Henter JI(1)(3).
Author information:
(1)Childhood Cancer Research Unit, Department of Women's and Children's Health,
Karolinska Institutet, Stockholm, Sweden.
(2)Department of Pediatrics, Eskilstuna Hospital, Eskilstuna, Sweden.
(3)Pediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska
University Hospital, Stockholm, Sweden.
(4)Center for Hematology and Regenerative Medicine, Department of Medicine
Huddinge, Karolinska Institutet, Stockholm, Sweden.
(5)Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
(6)Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska
Institutet, Stockholm, Sweden.
(7)Department of Clinical Pathology and Cancer Diagnostics, Karolinska
University Laboratory, Stockholm, Sweden.
(8)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal,
Sweden.
(9)Department of Psychiatry and Neurochemistry, Institute of Neuroscience and
Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal,
Sweden.
(10)UK Dementia Research Institute at UCL, London, UK.
(11)Department of Neurodegenerative Disease, UCL Institute of Neurology, London,
UK.
(12)Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
Patients with Langerhans cell histiocytosis (LCH) may develop progressive
neurodegeneration in the central nervous system (ND-CNS-LCH). Neurofilament
light protein (NFL) in cerebrospinal fluid (CSF) is a promising biomarker to
detect and monitor ND-CNS-LCH. We compared paired samples of NFL in plasma
(p-NFL) and CSF in 10 patients (19 samples). Nine samples had abnormal CSF-NFL
(defined as ≥380 ng/l) with corresponding p-NFL ≥ 2 ng/l. Ten samples had
CSF-NFL < 380 ng/l; eight (80%) with p-NFL < 2 ng/l (p < 0.001; Fisher's exact
test). Thus, our results suggest that p-NFL may be used to screen for
ND-CNS-LCH. Further studies are encouraged, including the role of p-NFL for
monitoring of ND-CNS-LCH.
© 2022 The Authors. British Journal of Haematology published by British Society
for Haematology and John Wiley & Sons Ltd.
DOI: 10.1111/bjh.18247
PMCID: PMC9420236
PMID: 35582775 [Indexed for MEDLINE]
Conflict of interest statement: HZ has served at scientific advisory boards
and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics,
AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics,
Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet
Therapeutics, and Wave, has given lectures in symposia sponsored by
Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co‐founder of
Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU
Ventures Incubator Program (outside submitted work). KB has served as a
consultant, at advisory boards, or at data monitoring committees for Abcam,
Axon, BioArctic, Biogen, Julius Clinical, Lilly, MagQu, Novartis, Roche
Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker
Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator
Program, all outside the submitted work. JIH has served as a consultant for
Sobi, outside the submitted work. The other authors have no conflicts of
interest to declare.
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http://www.ncbi.nlm.nih.gov/pubmed/35575811
|
1. J Neurol. 2022 Sep;269(9):5085-5092. doi: 10.1007/s00415-022-11165-0. Epub
2022 May 16.
Elevated serum Neurofilament Light chain (NfL) as a potential biomarker of
neurological involvement in Myotonic Dystrophy type 1 (DM1).
Nicoletti TF(#)(1)(2), Rossi S(#)(1)(2), Vita MG(1)(2), Perna A(1)(2), Guerrera
G(3), Lino F(1)(2), Iacovelli C(4), Di Natale D(1)(2), Modoni A(1)(2),
Battistini L(3), Silvestri G(5)(6).
Author information:
(1)Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo F.
Vito 1, 00168, Rome, Italy.
(2)UOC Neurologia - Dipartimento Scienze dell'Invecchiamento, Neurologiche,
Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli
IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy.
(3)Unità di Neuroimmunologia, Fondazione Santa Lucia IRCCS, Rome, Italy.
(4)UOC Riabilitazione e Medicina Fisica-Dipartimento Scienze
dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione
Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
(5)Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo F.
Vito 1, 00168, Rome, Italy. [email protected].
(6)UOC Neurologia - Dipartimento Scienze dell'Invecchiamento, Neurologiche,
Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli
IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy.
[email protected].
(#)Contributed equally
BACKGROUND: Cognitive and behavioural symptoms due to involvement of the central
nervous system (CNS) are among the main clinical manifestations of Myotonic
Dystrophy type 1 (DM1). Such symptoms affect patients' quality of life and
disease awareness, impacting on disease prognosis by reducing compliance to
medical treatments. Therefore, CNS is a key therapeutic target in DM1. Deeper
knowledge of DM1 pathogenesis is prompting development of potential
disease-modifying therapies: as DM1 is a rare, multisystem and slowly
progressive disease, there is need of sensitive, tissue-specific prognostic and
monitoring biomarkers in view of forthcoming clinical trials. Circulating
Neurofilament light chain (NfL) levels have been recognized as a sensitive
prognostic and monitoring biomarker of neuroaxonal damage in various CNS
disorders.
METHODS: We performed a cross-sectional study in a cohort of 40 adult DM1
patients, testing if serum NfL might be a potential biomarker of CNS involvement
also in DM1. Moreover, we collected cognitive data, brain MRI, and other
DM1-related diagnostic findings for correlation studies.
RESULTS: Mean serum NfL levels resulted significantly higher in DM1
(25.32 ± 28.12 pg/ml) vs 22 age-matched healthy controls (6.235 ± 0.4809 pg/ml).
Their levels positively correlated with age, and with one cognitive test (Rey's
Auditory Verbal learning task). No correlations were found either with other
cognitive data, or diagnostic parameters in the DM1 cohort.
CONCLUSIONS: Our findings support serum NfL as a potential biomarker of CNS
damage in DM1, which deserves further evaluation on larger cross-sectional and
longitudinal studies to test its ability in assessing brain disease severity
and/or progression.
© 2022. The Author(s).
DOI: 10.1007/s00415-022-11165-0
PMCID: PMC9363395
PMID: 35575811 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/35959400
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1. Front Neurol. 2022 Jul 25;13:935382. doi: 10.3389/fneur.2022.935382.
eCollection 2022.
Development of a Highly Sensitive Neurofilament Light Chain Assay on an
Automated Immunoassay Platform.
Lee S(1), Plavina T(2), Singh CM(2), Xiong K(2), Qiu X(1), Rudick RA(2),
Calabresi PA(3), Stevenson L(2), Graham D(2), Raitcheva D(2), Green C(1), Matias
M(1), Uzgiris AJ(1).
Author information:
(1)Siemens Healthcare Laboratory, LLC, Berkeley, CA, United States.
(2)Biogen, Cambridge, MA, United States.
(3)Department of Neurology, Johns Hopkins University School of Medicine,
Baltimore, MD, United States.
BACKGROUND: Neurofilament light chain (NfL) is an axonal cytoskeletal protein
that is released into the extracellular space following neuronal or axonal
injury associated with neurological conditions such as multiple sclerosis (MS),
amyotrophic lateral sclerosis (ALS), and other diseases. NfL is detectable in
the cerebrospinal fluid (CSF) and blood. Numerous studies on MS have
demonstrated that NfL is correlated with disease activity, predicts disease
progression, and is reduced by treatment with MS disease-modifying drugs, making
NfL an attractive candidate to supplement existing clinical and imaging measures
in MS. However, for NfL to achieve its potential as a clinically useful
biomarker for clinical decision-making or drug development, a standardized,
practical, and widely accessible assay is needed. Our objective was to develop a
novel NfL assay on an automated, globally available immunoassay platform and
validate its performance.
METHODS: A prototype NfL assay was first developed and evaluated on the ADVIA
Centaur® XP immunoassay system from Siemens Healthineers. The lower limit of
quantitation (LLoQ), within-lab precision, assay range, cross-reactivity with
neurofilament medium and heavy chains, and effect of interfering substances were
determined. NfL assay values in serum and CSF were compared with radiological
and clinical disease activity measures in patients with MS and ALS,
respectively. This assay was further optimized to utilize serum, plasma, and CSF
sample types on the Atellica® IM system and transferred to Siemens' CLIA
laboratory where it was analytically validated as a laboratory-developed test
(LDT).
RESULTS: In this study, an LLoQ of 1.85 pg/mL, within-lab precision <6%, and an
assay range of up to 646 pg/mL were demonstrated with the serum prototype assay.
Cross-reactivity of <0.7% with the neurofilament medium and heavy chains was
observed. Serum and CSF NfL assay values were associated with radiological and
clinical disease activity measures in patients with MS and ALS, respectively.
The optimized version of the NfL assay demonstrated specimen equivalence with
additional plasma tube types and was analytically validated as an LDT.
CONCLUSION: The analytical performance of the NfL assay fulfilled all acceptance
criteria; therefore, we suggest that the assay is acceptable for use in both
research and clinical practice settings to determine elevated NfL levels in
patients.
Copyright © 2022 Lee, Plavina, Singh, Xiong, Qiu, Rudick, Calabresi, Stevenson,
Graham, Raitcheva, Green, Matias and Uzgiris.
DOI: 10.3389/fneur.2022.935382
PMCID: PMC9359312
PMID: 35959400
Conflict of interest statement: SL is an employee of Siemens Healthcare
Laboratory, LLC. TP, KX, and RR was an employee of Biogen Inc. at the time of
the study. TP is currently an employee of Takeda. CS, DG, and DR are employees
of Biogen Inc. XQ, CG, and MM was an employee of Siemens Healthcare Laboratory,
LLC, at the time of the study. AU is an employee of Siemens Healthcare
Laboratory, LLC, has supervised the work of SL, XQ, and MM, and owns shares of
Siemens Healthineers AG stocks. Biogen was involved in the writing and editorial
support of this article. The remaining authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/35750882
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1. Sci Rep. 2022 Jun 24;12(1):10726. doi: 10.1038/s41598-022-14291-x.
Neurofilament light chain plasma levels are associated with area of brain damage
in experimental cerebral malaria.
Wai CH(1)(2), Jin J(1)(2), Cyrklaff M(2), Genoud C(3), Funaya C(4), Sattler
J(2), Maceski A(5), Meier S(5), Heiland S(1), Lanzer M(2), Frischknecht F(2)(6),
Kuhle J(5), Bendszus M(1), Hoffmann A(7)(8).
Author information:
(1)Department of Neuroradiology, Heidelberg University Hospital, Heidelberg,
Germany.
(2)Centre for Infectious Diseases, Parasitology Unit, Heidelberg University
Hospital, Heidelberg, Germany.
(3)Electron Microscopy Facility, Faculty of Biology and Medicine, University of
Lausanne, Lausanne, Switzerland.
(4)Electron Microscopy Core Facility, Heidelberg University, Heidelberg,
Germany.
(5)Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical
Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel,
University of Basel, Basel, Switzerland.
(6)German Center for Infection Research (DZIF), Heidelberg, Germany.
(7)Department of Neuroradiology, Heidelberg University Hospital, Heidelberg,
Germany. [email protected].
(8)Department of Neuroradiology, University Institute of Diagnostic and
Interventional Neuroradiology, University Hospital Bern, Inselspital, University
of Bern, Freiburgstrasse, 3010, Bern, Switzerland. [email protected].
Neurofilament light chain (NfL), released during central nervous injury, has
evolved as a powerful serum marker of disease severity in many neurological
disorders, including infectious diseases. So far NfL has not been assessed in
cerebral malaria in human or its rodent model experimental cerebral malaria
(ECM), a disease that can lead to fatal brain edema or reversible brain edema.
In this study we assessed if NfL serum levels can also grade disease severity in
an ECM mouse model with reversible (n = 11) and irreversible edema (n = 10).
Blood-brain-barrier disruption and brain volume were determined by magnetic
resonance imaging. Neurofilament density volume as well as structural integrity
were examined by electron microscopy in regions of most severe brain damage
(olfactory bulb (OB), cortex and brainstem). NfL plasma levels in mice with
irreversible edema (317.0 ± 45.01 pg/ml) or reversible edema
(528.3 ± 125.4 pg/ml) were significantly increased compared to controls
(103.4 ± 25.78 pg/ml) by three to five fold, but did not differ significantly in
mice with reversible or irreversible edema. In both reversible and irreversible
edema, the brain region most affected was the OB with highest level of
blood-brain-barrier disruption and most pronounced decrease in neurofilament
density volume, which correlated with NfL plasma levels (r = - 0.68, p = 0.045).
In cortical and brainstem regions neurofilament density was only decreased in
mice with irreversible edema and strongest in the brainstem. In reversible edema
NfL plasma levels, MRI findings and neurofilament volume density normalized at
3 months' follow-up. In conclusion, NfL plasma levels are elevated during ECM
confirming brain damage. However, NfL plasma levels fail short on reliably
indicating on the final outcomes in the acute disease stage that could be either
fatal or reversible. Increased levels of plasma NfL during the acute disease
stage are thus likely driven by the anatomical location of brain damage, the
olfactory bulb, a region that serves as cerebral draining pathway into the nasal
lymphatics.
© 2022. The Author(s).
DOI: 10.1038/s41598-022-14291-x
PMCID: PMC9232608
PMID: 35750882 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
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http://www.ncbi.nlm.nih.gov/pubmed/29630554
|
1. J Alzheimers Dis. 2018;63(2):479-487. doi: 10.3233/JAD-180025.
Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load
and Cognitive Performance in Cognitively Normal Elderly Participants.
Chatterjee P(1)(2)(3), Goozee K(1)(2)(3)(4)(5)(6), Sohrabi HR(1)(2)(5)(7), Shen
K(8), Shah T(1)(2)(7), Asih PR(3)(9), Dave P(1)(4), ManYan C(4), Taddei K(2)(7),
Chung R(1), Zetterberg H(10)(11)(12)(13), Blennow K(10)(11), Martins
RN(1)(2)(3)(5)(7)(6).
Author information:
(1)Department of Biomedical Sciences, Macquarie University, North Ryde, NSW,
Australia.
(2)School of Medical Health and Sciences, Edith Cowan University, Joondalup, WA,
Australia.
(3)KaRa Institute of Neurological Disease, Sydney, Macquarie Park, Australia.
(4)Department of Clinical Research, Anglicare, Sydney, Castle Hill, NSW,
Australia.
(5)School of Psychiatry and Clinical Neurosciences, University of Western
Australia, Crawley, WA, Australia.
(6)The Cooperative Research Centre for Mental Health, Carlton South, Australia.
(7)Australian Alzheimer Research Foundation, Nedlands, WA, Australia.
(8)Australian eHealth Research Centre, CSIRO, Floreat, Australia.
(9)School of Medical Sciences, University of New South Wales, Kensington, NSW,
Australia.
(10)Department of Psychiatry and Neurochemistry, Institute of Neuroscience and
Physiology, University of Gothenburg, Mölndal, Sweden.
(11)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital,
Mölndal, Sweden.
(12)Department of Molecular Neuroscience, UCL Institute of Neurology, Queen
Square, London, UK.
(13)UK Dementia Research Institute at UCL, London, UK.
BACKGROUND: The disruption of neurofilament, an axonal cytoskeletal protein, in
neurodegenerative conditions may result in neuronal damage and its release into
the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament
light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal
fluid and blood.
OBJECTIVE: Investigate the association of plasma NFL with preclinical-AD
features, such as high neocortical amyloid-β load (NAL) and subjective memory
complaints, and cognitive performance in cognitively normal older adults.
METHODS: Plasma NFL concentrations were measured employing the single molecule
array platform in participants from the Kerr Anglican Retirement Village
Initiative in Ageing Health cohort, aged 65- 90 years. Participants underwent a
battery of neuropsychological testing to evaluate cognitive performance and were
categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) assessed via
PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51,
nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment
Clinic- Questionnaire.
RESULTS: Plasma NFL inversely correlated with cognitive performance. No
significant difference in NFL was observed between NAL+ and NAL- participants;
however, within APOEɛ4 non-carriers, higher NAL was observed in individuals with
NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally,
within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC.
CONCLUSION: Plasma NFL is inversely associated with cognitive performance in
elderly individuals. While plasma NFL may not reflect NAL in individuals with
normal global cognition, the current observations indicate that onset of axonal
injury, reflected by increased plasma NFL, within the preclinical phase of AD
may contribute to the pathogenesis of AD.
DOI: 10.3233/JAD-180025
PMID: 29630554 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35638376
|
1. Eur J Neurol. 2022 Sep;29(9):2810-2822. doi: 10.1111/ene.15428. Epub 2022 Jun
20.
Neurofilament light chain and total tau in the differential diagnosis and
prognostic evaluation of acute and chronic inflammatory polyneuropathies.
Kmezic I(1)(2), Samuelsson K(1)(2), Finn A(2), Upate Z(3), Blennow K(4)(5),
Zetterberg H(4)(5)(6)(7)(8), Press R(1)(2).
Author information:
(1)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm,
Sweden.
(2)Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
(3)Department of Neurophysiology, Karolinska University Hospital, Stockholm,
Sweden.
(4)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal,
Sweden.
(5)Department of Psychiatry and Neurochemistry, Institute of Neuroscience and
Psychology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
(6)Department of Neurodegenerative Disease, UCL Institute of Neurology, London,
UK.
(7)UK Dementia Research Institute at UCL, London, UK.
(8)Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
BACKGROUND AND PURPOSE: To investigate the diagnostic and prognostic value of
axonal injury biomarkers in patients with inflammatory polyneuropathies.
METHODS: Neurofilament light chain (NfL) and total tau (T-tau) were measured in
the cerebrospinal fluid (CSF) and plasma in 41 patients with Guillain-Barré
syndrome (GBS), 32 patients with chronic inflammatory demyelinating
polyneuropathy (CIDP), 10 with paraproteinemia-related demyelinating
polyneuropathy (PDN), and 8 with multifocal motor neuropathy (MMN), in
comparison with 39 disease-free controls and 59 other controls. Outcome was
measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause
and Treatment (INCAT) disability score.
RESULTS: Neurofilament light chain levels in CSF and plasma were higher in GBS,
CIDP, and PDN vs. disease-free controls. Patients with MMN had higher NfL levels
in plasma vs. disease-free controls, but lower levels in CSF and plasma vs.
patients with amyotrophic lateral sclerosis (ALS). T-tau levels in plasma were
higher in GBS, CIDP, PDN, and MMN vs. all control groups. Neurofilament light
chain levels in CSF and plasma in patients with GBS correlated with GBS-ds, as
higher levels were associated with inability to run after 6 and 12 months. NfL
levels in CSF and plasma in CIDP did not correlate significantly with outcome.
CONCLUSIONS: Acute and chronic inflammatory neuropathies are associated with an
increase in levels of NfL in CSF and plasma, but NfL is validated as a
prognostic biomarker only in GBS. NfL could be used in differentiating patients
with MMN from ALS. T-tau in plasma is a novel biomarker that could be used in a
diagnostic assessment of patients with acute and chronic inflammatory
polyneuropathies.
© 2022 The Authors. European Journal of Neurology published by John Wiley &
Sons Ltd on behalf of European Academy of Neurology.
DOI: 10.1111/ene.15428
PMCID: PMC9542418
PMID: 35638376 [Indexed for MEDLINE]
Conflict of interest statement: Ivan Kmezic declares no conflicts of interest.
Kristin Samuelsson has served on scientific advisory boards and/or as a
consultant for Akcea Theurapeutics, Inc. and Alnylam Pharmaceuticals. Anja Finn
declares no conflict of interest. Zane Upate declares no conflicts of interest.
Kaj Blennow has served as a consultant, on advisory boards, or on data
monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius
Clinical, Lilly, MagQu, Novartis, Pharmatrophix, Prothena, Roche Diagnostics,
and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in
Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program,
outside the work presented in this article. Kaj Blennow is supported by the
Swedish Research Council (#2017–00915), the Alzheimer Drug Discovery Foundation
(ADDF), USA (#RDAPB‐201809‐2016615), the Swedish Alzheimer Foundation
(#AF‐742881), Hjärnfonden, Sweden (#FO2017‐0243), the Swedish state under the
agreement between the Swedish government and the County Councils, the
ALF‐agreement (#ALFGBG‐715986), the European Union Joint Program for
Neurodegenerative Disorders (JPND2019‐466‐236), the National Institutes of
Health (NIH), USA (grant #1R01AG068398–01), and the Alzheimer's Association 2021
Zenith Award (ZEN‐21‐848495). Henrik Zetterberg has served on scientific
advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery
Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics,
Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet
Therapeutics, and Wave, has given lectures at symposia sponsored by
Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co‐founder of
Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU
Ventures Incubator Program (outside the submitted work). Henrik Zetterberg is a
Wallenberg Scholar supported by grants from the Swedish Research Council
(#2018–02532), the European Research Council (#681712), Swedish State Support
for Clinical Research (#ALFGBG‐720931), the Alzheimer Drug Discovery Foundation
(ADDF), USA (#201809–2016862), the AD Strategic Fund and the Alzheimer's
Association (#ADSF‐21‐831376‐C, #ADSF‐21‐831381‐C, and #ADSF‐21‐831377‐C), the
Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla
Tjänarinnor, Hjärnfonden, Sweden (#FO2019‐0228), the European Union's Horizon
2020 research and innovation programme under the Marie Skłodowska‐Curie grant
agreement No. 860197 (MIRIADE), European Union Joint Program for
Neurodegenerative Disorders (JPND2021‐00694), and the UK Dementia Research
Institute at UCL. Rayomand Press declares no conflicts of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/33108404
|
1. PLoS One. 2020 Oct 27;15(10):e0236384. doi: 10.1371/journal.pone.0236384.
eCollection 2020.
Plasma neurofilament light protein correlates with diffusion tensor imaging
metrics in frontotemporal dementia.
Spotorno N(1)(2), Lindberg O(3), Nilsson C(4), Landqvist Waldö M(5), van Westen
D(6), Nilsson K(2), Vestberg S(7), Englund E(8), Zetterberg H(9)(10)(11)(12),
Blennow K(9)(10), Lätt J(13), Markus N(6), Lars-Olof W(3), Alexander S(2).
Author information:
(1)Department of Neurology, Penn Frontotemporal Degeneration Center, University
of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of
America.
(2)Department of Clinical Sciences, Clinical Memory Research Unit, Lund
University, Malmö, Sweden.
(3)Division of Clinical Geriatrics, Karolinska Institute, Stockholm, Sweden.
(4)Division of Neurology, Department of Clinical Sciences, Lund University,
Lund, Sweden.
(5)Department of clinical Sciences, Clinical Sciences Helsingborg, Lund, Lund
University, Lund, Sweden.
(6)Department of Diagnostic Radiology, Clinical Sciences, Lund University, Lund,
Sweden.
(7)Department of Psychology, Lund University, Lund, Sweden.
(8)Division of Pathology, Department of Clinical Sciences, Lund, Sweden.
(9)Department of Psychiatry and Neurochemistry, Institute of Neuroscience &
Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal,
Sweden.
(10)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital,
Mölndal, Sweden.
(11)Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen
Square, London, United Kingdom.
(12)UK Dementia Research Institute at UCL, London, United Kingdom.
(13)Center for Medical Imaging and Physiology, Skåne University Hospital, Lund,
Sweden.
Neurofilaments are structural components of neurons and are particularly
abundant in highly myelinated axons. The levels of neurofilament light chain
(NfL) in both cerebrospinal fluid (CSF) and plasma have been related to
degeneration in several neurodegenerative conditions including frontotemporal
dementia (FTD) and NfL is currently considered as the most promising diagnostic
and prognostic fluid biomarker in FTD. Although the location and function of
filaments in the healthy nervous system suggests a link between increased NfL
and white matter degeneration, such a claim has not been fully elucidated in
vivo, especially in the context of FTD. The present study provides evidence of
an association between the plasma levels of NfL and white matter involvement in
behavioral variant FTD (bvFTD) by relating plasma concentration of NfL to
diffusion tensor imaging (DTI) metrics in a group of 20 bvFTD patients. The
results of both voxel-wise and tract specific analysis showed that increased
plasma NfL concentration is associated with a reduction in fractional anisotropy
(FA) in a widespread set of white matter tracts including the superior
longitudinal fasciculus, the fronto-occipital fasciculus the anterior thalamic
radiation and the dorsal cingulum bundle. Plasma NfL concentration also
correlated with cortical thinning in a portion of the right medial prefrontal
cortex and of the right lateral orbitofrontal cortex. These results support the
hypothesis that blood NfL levels reflect the global level of neurodegeneration
in bvFTD and help to advance our understanding of the association between this
blood biomarker for FTD and the disease process.
DOI: 10.1371/journal.pone.0236384
PMCID: PMC7591030
PMID: 33108404 [Indexed for MEDLINE]
Conflict of interest statement: HZ has served at scientific advisory boards for
Denali, Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in
symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of
Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU
Ventures Incubator Program. KB has served as a consultant, at advisory boards,
or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius
Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers,
and is also a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS).
These do not alter our adherence to PLOS ONE policies on sharing data and
materials.
|
http://www.ncbi.nlm.nih.gov/pubmed/35075461
|
1. medRxiv [Preprint]. 2022 Jan 14:2022.01.13.22269244. doi:
10.1101/2022.01.13.22269244.
Prognostic Value of Serum/Plasma Neurofilament Light Chain for COVID-19
Associated Mortality.
Masvekar RR(1), Kosa P(1), Jin K(1), Dobbs K(1), Stack MA(1), Castagnoli R(1),
Quaresima V(2), Su HC(1), Imberti L(2), Notarangelo LD(1), Bielekova B(1).
Author information:
(1)National Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD.
(2)CREA Laboratory (AIL Center for Hemato-Oncologic Research), Diagnostic
Department, ASST Spedali Civili di Brescia, Brescia, Italy.
Update in
Ann Clin Transl Neurol. 2022 May;9(5):622-632. doi: 10.1002/acn3.51542.
Given the continued spread of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), early predictors of coronavirus disease 19 (COVID-19) mortality
might improve patients’ outcomes. Increased levels of circulating
neurofilament light chain (NfL), a biomarker of neuro-axonal injury, have been
observed in patients with severe COVID-19. We investigated whether NfL provides
non-redundant clinical value to previously identified predictors of COVID-19
mortality. We measured serum or plasma NfL concentrations in a blinded fashion
in 3 cohorts totaling 338 COVID-19 patients. In cohort 1, we found significantly
elevated NfL levels only in critically ill COVID-19 patients compared to healthy
controls. Longitudinal cohort 2 data showed that NfL is elevated late in the
course of the disease, following two other prognostic markers of COVID-19:
decrease in absolute lymphocyte count (ALC) and increase in lactate
dehydrogenase (LDH). Significant correlations between LDH and ALC abnormalities
and subsequent rise of NfL implicate multi-organ failure as a likely cause of
neuronal injury at the later stages of COVID-19. Addition of NfL to age and
gender in cohort 1 significantly improved the accuracy of mortality prediction
and these improvements were validated in cohorts 2 and 3. In conclusion,
although substantial increase in serum/plasma NfL reproducibly enhances COVID-19
mortality prediction, NfL has clinically meaningful prognostic value only close
to death, which may be too late to alter medical management. When combined with
other prognostic biomarkers, rising longitudinal NfL measurements triggered by
LDH and ALC abnormalities would identify patients at risk of COVID-19 associated
mortality who might still benefit from escalated care.
DOI: 10.1101/2022.01.13.22269244
PMCID: PMC8786234
PMID: 35075461
|
http://www.ncbi.nlm.nih.gov/pubmed/30055655
|
1. Alzheimers Res Ther. 2018 Jul 28;10(1):71. doi: 10.1186/s13195-018-0404-9.
Plasma neurofilament light as a potential biomarker of neurodegeneration in
Alzheimer's disease.
Lewczuk P(1)(2), Ermann N(3), Andreasson U(4)(5), Schultheis C(6), Podhorna
J(7), Spitzer P(3), Maler JM(3), Kornhuber J(3), Blennow K(4)(5), Zetterberg
H(4)(5)(8)(9).
Author information:
(1)Department of Psychiatry and Psychotherapy, Lab for Clinical Neurochemistry
and Neurochemical Dementia Diagnostics, Universitätsklinikum Erlangen, and
Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054,
Erlangen, Germany. [email protected].
(2)Department of Neurodegeneration Diagnostics, Department of Biochemical
Diagnostics, Medical University of Bialystok, University Hospital of Bialystok,
Bialystok, Poland. [email protected].
(3)Department of Psychiatry and Psychotherapy, Lab for Clinical Neurochemistry
and Neurochemical Dementia Diagnostics, Universitätsklinikum Erlangen, and
Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054,
Erlangen, Germany.
(4)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal,
Sweden.
(5)Department of Psychiatry and Neurochemistry, Institute of Neuroscience and
Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal,
Sweden.
(6)Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
(7)Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany.
(8)Department of Molecular Neuroscience, UCL Institute of Neurology, Queen
Square, London, UK.
(9)UK Dementia Research Institute at UCL, London, UK.
BACKGROUND: A growing body of evidence suggests that the plasma concentration of
the neurofilament light chain (NfL) might be considered a plasma biomarker for
the screening of neurodegeneration in Alzheimer's disease (AD).
METHODS: With a single molecule array method (Simoa, Quanterix), plasma NfL
concentrations were measured in 99 subjects with AD at the stage of mild
cognitive impairment (MCI-AD; n = 25) or at the stage of early dementia (ADD;
n = 33), and in nondemented controls (n = 41); in all patients, the clinical
diagnoses were in accordance with the results of the four core cerebrospinal
fluid (CSF) biomarkers (amyloid β (Aβ)1-42, Aβ42/40, Tau, and pTau181),
interpreted according to the Erlangen Score algorithm. The influence of
preanalytical storage procedures on the NfL in plasma was tested on samples
exposed to six different conditions.
RESULTS: NfL concentrations significantly increased in the samples exposed to
more than one freezing/thawing cycle, and in those stored for 5 days at room
temperature or at 4 °C. Compared with the control group of nondemented subjects
(22.0 ± 12.4 pg/mL), the unadjusted plasma NfL concentration was highly
significantly higher in the MCI-AD group (38.1 ± 15.9 pg/mL, p < 0.005) and even
further elevated in the ADD group (49.1 ± 28.4 pg/mL; p < 0.001). A significant
association between NfL and age (ρ = 0.65, p < 0.001) was observed; after
correcting for age, the difference in NfL concentrations between AD and controls
remained significant (p = 0.044). At the cutoff value of 25.7 pg/mL,
unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82,
respectively. Unadjusted correlation between plasma NfL and Mini Mental State
Examination (MMSE) across all patients was moderate but significant (r = -0.49,
p < 0.001). We observed an overall significant correlation between plasma NfL
and the CSF biomarkers, but this correlation was not observed within the
diagnostic groups.
CONCLUSIONS: This study confirms increased concentrations of plasma NfL in
patients with Alzheimer's disease compared with nondemented controls.
DOI: 10.1186/s13195-018-0404-9
PMCID: PMC6064615
PMID: 30055655 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The
ethical committee of the University of Erlangen-Nuremberg approved the study,
and all patients or their caregivers gave their written consent. CONSENT FOR
PUBLICATION: Not applicable. COMPETING INTERESTS: PL has received consultation
and/or lecture honoraria from IBL International, Fujirebio Europe, AJ
Roboscreen, and Roche. KB has served as a consultant or on advisory boards for
Alzheon, BioArctic, Biogen, Eli Lilly, Fujirebio Europe, IBL International,
Merck, Novartis, Pfizer, and Roche Diagnostics. KB and HZ are cofounders of
Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company
at the University of Gothenburg. HZ has served on advisory boards of Eli Lilly
and Roche Diagnostics and has received travel support from Teva. CS and JP are
full-time employees of Boehringer Ingelheim. All remaining authors declare that
they have no competing interests. PUBLISHER’S NOTE: Springer Nature remains
neutral with regard to jurisdictional claims in published maps and institutional
affiliations.
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http://www.ncbi.nlm.nih.gov/pubmed/33636389
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1. Neurobiol Dis. 2021 Jun;153:105311. doi: 10.1016/j.nbd.2021.105311. Epub 2021
Feb 23.
Plasma neurofilament light chain predicts cerebellar atrophy and clinical
progression in spinocerebellar ataxia.
Coarelli G(1), Darios F(2), Petit E(2), Dorgham K(3), Adanyeguh I(2), Petit
E(1), Brice A(2), Mochel F(1), Durr A(4).
Author information:
(1)Sorbonne Université, ICM (Paris Brain Institute), AP-HP, INSERM, CNRS,
University Hospital Pitié-Salpêtrière, Paris, France; APHP Department of
Genetics, Pitié-Salpêtrière University Hospital, Paris, France.
(2)Sorbonne Université, ICM (Paris Brain Institute), AP-HP, INSERM, CNRS,
University Hospital Pitié-Salpêtrière, Paris, France.
(3)Sorbonne Université, INSERM, CNRS, Centre d'Immunologie et des Maladies
Infectieuses-Paris (CIMI-Paris), F-75013 Paris, France.
(4)Sorbonne Université, ICM (Paris Brain Institute), AP-HP, INSERM, CNRS,
University Hospital Pitié-Salpêtrière, Paris, France; APHP Department of
Genetics, Pitié-Salpêtrière University Hospital, Paris, France. Electronic
address: [email protected].
Neurofilament light chain (NfL) is a marker of brain atrophy and predictor of
disease progression in rare diseases such as Huntington Disease, but also in
more common neurological disorders such as Alzheimer's disease. The aim of this
study was to measure NfL longitudinally in autosomal dominant spinocerebellar
ataxias (SCAs) and establish correlation with clinical and imaging parameters.
We enrolled 62 pathological expansions carriers (17 SCA1, 13 SCA2, 19 SCA3, and
13 SCA7) and 19 age-matched controls in a prospective biomarker study between
2011 and 2015 and followed for 24 months at the Paris Brain Institute. We
performed neurological examination, brain 3 T MRI and plasma NfL measurements
using an ultrasensitive single-molecule array at baseline and at the two-year
follow-up visit. We evaluated NfL correlations with ages, CAG repeat sizes,
clinical scores and volumetric brain MRIs. NfL levels were significantly higher
in SCAs than controls at both time points (p < 0.001). Age-adjusted NfL levels
were significantly correlated at baseline with clinical scores (p < 0.01). We
identified optimal NfL cut-off concentrations to differentiate controls from
carriers for each genotype (SCA1 16.87 pg/mL, SCA2, 19.1 pg/mL, SCA3
16.04 pg/mL, SCA7 16.67 pg/mL). For all SCAs, NfL concentration was stable over
two years (p = 0.95) despite a clinical progression (p < 0.0001). Clinical
progression between baseline and follow-up was associated with higher NfL
concentrations at baseline (p = 0.04). Of note, all premanifest carriers with
NfL levels close to cut off concentrations had signs of the disease at
follow-up. For all SCAs, the higher the observed NfL, the lower the pons volume
at baseline (p < 0.01) and follow-up (p = 0.02). Higher NfL levels at baseline
in all SCAs predicted a decrease in cerebellar volume (p = 0.03). This result
remained significant for SCA2 only among all genotypes (p = 0.02). Overall,
plasma NfL levels at baseline in SCA expansion carriers predict cerebellar
volume change and clinical score progression. NfL levels might help refine
inclusion criteria for clinical trials in carriers with very subtle signs.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2021.105311
PMID: 33636389 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/34311152
|
1. J Neuroimmunol. 2021 Sep 15;358:577662. doi: 10.1016/j.jneuroim.2021.577662.
Epub 2021 Jul 13.
Association between plasma neurofilament light chain levels and cognitive
function in patients with Parkinson's disease.
Zhu Y(1), Yang B(2), Wang F(1), Liu B(1), Li K(1), Yin K(1), Yin WF(1), Zhou
C(1), Tian S(3), Ren H(1), Pang A(4), Yang X(5).
Author information:
(1)Department of Geriatric Neurology, First Affiliated Hospital of Kunming
Medical University, Kunming, Yunnan Province 650032, PR China.
(2)Department of Neurology, Seventh People's Hospital of Chengdu, Chengdu,
Sichuan Province 690041, PR China.
(3)Department of Neurology, West China Hospital, Sichuan University, PR China.
(4)Department of Neurology, First Affiliated Hospital of Kunming Medical
University, Kunming, Yunnan Province 650032, PR China. Electronic address:
[email protected].
(5)Department of Geriatric Neurology, First Affiliated Hospital of Kunming
Medical University, Kunming, Yunnan Province 650032, PR China. Electronic
address: [email protected].
This study investigated the potential association between levels of plasma
neurofilament light chain (NfL) and cognitive function in patients suffering
from Parkinson's disease (PD) in P.R. China.We collected a total of 168
participants (130 PD patients and 38 healthy controls),and evaluated the
relationship of plasma NfL levels with cognitive dysfunction in PD patients. Our
results shown that plasma NfL levels increased with an increase in cognitive
impairment across the three groups of PD patients: PD with normal cognition
(PD-NC), 17.9 ± 8.9 pg/ml; PD with mild cognitive impairment
(PD-MCI),21.9 ± 10.3 pg/ml; and PD dementia (PDD), 35.7 ± 21.7 pg/ml. Higher
MMSE scores were associated with lower plasma NfL levels (r = -0.49, 95% CI
-0.61 to -0.34, p < 0.0001). Our results associating plasma NfL levels with
cognitive dysfunction in PD are consistent with previous studies carried out in
several countries/district, based on our meta-analysis.
Copyright © 2021 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jneuroim.2021.577662
PMID: 34311152 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/36173566
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1. Methods Mol Biol. 2023;2577:65-81. doi: 10.1007/978-1-0716-2724-2_5.
ATAC-Seq Analysis of Accessible Chromatin: From Experimental Steps to Data
Analysis.
Tatara M(1), Ikeda T(1), Namekawa SH(2), Maezawa S(3).
Author information:
(1)Department of Applied Biological Science, Tokyo University of Science, Chiba,
Japan.
(2)Department of Microbiology and Molecular Genetics, University of California
Davis, Davis, CA, USA. [email protected].
(3)Department of Applied Biological Science, Tokyo University of Science, Chiba,
Japan. [email protected].
Accessible chromatin often represents gene regulatory elements, including
promoters and enhancers, essential for gene expression. Assay for Transposase
Accessible Chromatin sequencing (ATAC-seq) is one of the most popular techniques
to investigate chromatin accessibility across the genome. Here we describe, step
by step, a series of optimized experimental methods and bioinformatics pipelines
for ATAC-seq analysis. As an example, we present an analysis of murine
spermatogenic cells: a method to isolate germ cells, a reaction step using Tn5
transposase to insert sequencing adapters into accessible DNA, a library
preparation method for high-throughput sequencing, and bioinformatics analysis
of sequencing data. Overall, we introduce a framework of ATAC-seq analysis that
can be applied to any cell population to identify cell-type-specific gene
regulatory elements and their cis-regulatory networks.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2724-2_5
PMID: 36173566 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36264486
|
1. Methods Mol Biol. 2023;2594:29-43. doi: 10.1007/978-1-0716-2815-7_3.
Genome-Wide Identification of Open Chromatin in Plants Using MH-Seq.
Zhang A(1), Li X(1), Zhao H(2), Jiang J(2)(3), Zhang W(4).
Author information:
(1)State Key Laboratory for Crop Genetics and Germplasm Enhancement, JCIC-MCP,
CIC-MCP, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China.
(2)Department of Plant Biology, Michigan State University, East Lansing, MI,
USA.
(3)Department of Horticulture, Michigan State University, East Lansing, MI, USA.
(4)State Key Laboratory for Crop Genetics and Germplasm Enhancement, JCIC-MCP,
CIC-MCP, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China.
[email protected].
Functional cis-regulatory elements (CREs) act as precise transcriptional
switches for fine-tuning gene transcription. Identification of CREs is critical
for understanding regulatory mechanisms of gene expression associated with
various biological processes in eukaryotes. It is well known that CREs reside in
open chromatin that exhibits hypersensitivity to enzyme cleavage and physical
shearing. Currently, high-throughput methodologies, such as DNase-seq, ATAC-seq,
and FAIRE-seq, have been widely applied in mapping open chromatin in various
eukaryotic genomes. More recently, differential MNase (micrococcal nuclease)
treatment has been successfully employed to map open chromatin in addition to
profiling nucleosome landscape in both mammalian and plant species. We have
developed a MNase hypersensitivity sequencing (MH-seq) technique in plants. The
MH-seq procedure includes plant nuclei fixation and purification, differential
treatments of purified nuclei with MNase, specific recovery of MNase-trimmed
small DNA fragments within 20~100 bp in length, and MH-seq library construction
followed by Illumina sequencing and data analysis. MH-seq has been successfully
applied for global identification of open chromatin in both Arabidopsis thaliana
and maize. It has been proven to be an attractive alternative for profiling open
chromatin. Thus, MH-seq is expected to be valuable in probing chromatin
accessibility on a genome-wide scale for other plants with sequenced genomes.
Moreover, MHS data allow to implement footprinting assays to unveil binding
sites of transcription factors.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2815-7_3
PMID: 36264486 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35796986
|
1. Methods Mol Biol. 2022;2533:127-145. doi: 10.1007/978-1-0716-2501-9_8.
Tethered MNase Structure Probing as Versatile Technique for Analyzing RNPs Using
Tagging Cassettes for Homologous Recombination in Saccharomyces cerevisiae.
Teubl F(#)(1), Schwank K(#)(1), Ohmayer U(1)(2), Griesenbeck J(3), Tschochner
H(4), Milkereit P(5).
Author information:
(1)Regensburg Center for Biochemistry (RCB), Institut für Biochemie, Genetik und
Mikrobiologie, Universität Regensburg, Regensburg, Germany.
(2)Evotec München GmbH, Martinsried, Germany.
(3)Regensburg Center for Biochemistry (RCB), Institut für Biochemie, Genetik und
Mikrobiologie, Universität Regensburg, Regensburg, Germany.
[email protected].
(4)Regensburg Center for Biochemistry (RCB), Institut für Biochemie, Genetik und
Mikrobiologie, Universität Regensburg, Regensburg, Germany.
[email protected].
(5)Regensburg Center for Biochemistry (RCB), Institut für Biochemie, Genetik und
Mikrobiologie, Universität Regensburg, Regensburg, Germany.
[email protected].
(#)Contributed equally
Micrococcal nuclease (MNase) originating from Staphylococcus aureus is a calcium
dependent ribo- and desoxyribonuclease which has endo- and exonucleolytic
activity of low sequence preference. MNase is widely used to analyze nucleosome
positions in chromatin by probing the enzyme's DNA accessibility in limited
digestion reactions. Probing reactions can be performed in a global way by
addition of exogenous MNase , or locally by "chromatin endogenous cleavage "
(ChEC ) reactions using MNase fusion proteins . The latter approach has recently
been adopted for the analysis of local RNA environments of MNase fusion proteins
which are incorporated in vivo at specific sites of ribonucleoprotein (RNP )
complexes. In this case, ex vivo activation of MNase by addition of calcium
leads to RNA cleavages in proximity to the tethered anchor protein thus
providing information about the folding state of its RNA environment.Here, we
describe a set of plasmids that can be used as template for PCR-based MNase
tagging of genes by homologous recombination in S. cerevisiae . The templates
enable both N- and C-terminal tagging with MNase in combination with linker
regions of different lengths and properties. In addition, an affinity tag is
included in the recombination cassettes which can be used for purification of
the particle of interest before or after induction of MNase cleavages in the
surrounding RNA or DNA. A step-by-step protocol is provided for tagging of a
gene of interest, followed by affinity purification of the resulting fusion
protein together with associated RNA and subsequent induction of local MNase
cleavages.
© 2022. The Author(s).
DOI: 10.1007/978-1-0716-2501-9_8
PMCID: PMC9761527
PMID: 35796986 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30064353
|
1. BMC Genomics. 2018 Jul 31;19(1):563. doi: 10.1186/s12864-018-4943-z.
ATAC2GRN: optimized ATAC-seq and DNase1-seq pipelines for rapid and accurate
genome regulatory network inference.
Pranzatelli TJF(1), Michael DG(1), Chiorini JA(2).
Author information:
(1)National Institute of Dental and Craniofacial Research, National Institutes
of Health, 10 Center Drive, Bethesda, MD, 20816, USA.
(2)National Institute of Dental and Craniofacial Research, National Institutes
of Health, 10 Center Drive, Bethesda, MD, 20816, USA.
[email protected].
Erratum in
BMC Genomics. 2019 Jan 15;20(1):44. doi: 10.1186/s12864-019-5441-7.
BACKGROUND: Chromatin accessibility profiling assays such as ATAC-seq and
DNase1-seq offer the opportunity to rapidly characterize the regulatory state of
the genome at a single nucleotide resolution. Optimization of molecular
protocols has enabled the molecular biologist to produce next-generation
sequencing libraries in several hours, leaving the analysis of sequencing data
as the primary obstacle to wide-scale deployment of accessibility profiling
assays. To address this obstacle we have developed an optimized and efficient
pipeline for the analysis of ATAC-seq and DNase1-seq data.
RESULTS: We executed a multi-dimensional grid-search on the NIH Biowulf
supercomputing cluster to assess the impact of parameter selection on biological
reproducibility and ChIP-seq recovery by analyzing 4560 pipeline configurations.
Our analysis improved ChIP-seq recovery by 15% for ATAC-seq and 3% for
DNase1-seq and determined that PCR duplicate removal improves biological
reproducibility by 36% without significant costs in footprinting transcription
factors. Our analyses of down sampled reads identified a point of diminishing
returns for increased library sequencing depth, with 95% of the ChIP-seq data of
a 200 million read footprinting library recovered by 160 million reads.
CONCLUSIONS: We present optimized ATAC-seq and DNase-seq pipelines in both
Snakemake and bash formats as well as optimal sequencing depths for ATAC-seq and
DNase-seq projects. The optimized ATAC-seq and DNase1-seq analysis pipelines,
parameters, and ground-truth ChIP-seq datasets have been made available for
deployment and future algorithmic profiling.
DOI: 10.1186/s12864-018-4943-z
PMCID: PMC6069842
PMID: 30064353 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The
authors declare no competing interests. PUBLISHER’S NOTE: Springer Nature
remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations.
|
http://www.ncbi.nlm.nih.gov/pubmed/31160376
|
1. Genome Res. 2019 Jun;29(6):969-977. doi: 10.1101/gr.245399.118. Epub 2019 Jun
3.
methyl-ATAC-seq measures DNA methylation at accessible chromatin.
Spektor R(1), Tippens ND(2), Mimoso CA(3), Soloway PD(4)(5).
Author information:
(1)Department of Molecular Biology and Genetics, Field of Genetics, Genomics,
and Development, Cornell University, Ithaca, New York 14853, USA.
(2)Tri-Institutional Training Program in Computational Biology and Medicine,
Cornell University, Ithaca, New York 14853, USA.
(3)College of Agricultural and Life Sciences, Cornell University, Ithaca, New
York 14853, USA.
(4)College of Veterinary Medicine, Department of Biomedical Sciences, Cornell
University, Ithaca, New York 14853, USA.
(5)College of Agriculture and Life Sciences, Division of Nutritional Sciences,
Cornell University, Ithaca, New York 14853, USA.
Chromatin features are characterized by genome-wide assays for nucleosome
location, protein binding sites, three-dimensional interactions, and
modifications to histones and DNA. For example, assay for transposase accessible
chromatin sequencing (ATAC-seq) identifies nucleosome-depleted (open) chromatin,
which harbors potentially active gene regulatory sequences; and bisulfite
sequencing (BS-seq) quantifies DNA methylation. When two distinct chromatin
features like these are assayed separately in populations of cells, it is
impossible to determine, with certainty, where the features are coincident in
the genome by simply overlaying data sets. Here, we describe methyl-ATAC-seq
(mATAC-seq), which implements modifications to ATAC-seq, including subjecting
the output to BS-seq. Merging these assays into a single protocol identifies the
locations of open chromatin and reveals, unambiguously, the DNA methylation
state of the underlying DNA. Such combinatorial methods eliminate the need to
perform assays independently and infer where features are coincident.
© 2019 Spektor et al.; Published by Cold Spring Harbor Laboratory Press.
DOI: 10.1101/gr.245399.118
PMCID: PMC6581052
PMID: 31160376 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29181276
|
1. PeerJ. 2017 Nov 22;5:e4040. doi: 10.7717/peerj.4040. eCollection 2017.
I-ATAC: interactive pipeline for the management and pre-processing of ATAC-seq
samples.
Ahmed Z(1), Ucar D(2).
Author information:
(1)Department of Genetics and Genome Sciences, University of Connecticut Health
Center, Farmington, CT, United States of America.
(2)The Jackson Laboratory For Genomic Medicine, Farmington, CT, United States of
America.
Assay for Transposase Accessible Chromatin (ATAC-seq) is an open chromatin
profiling assay that is adapted to interrogate chromatin accessibility from
small cell numbers. ATAC-seq surmounted a major technical barrier and enabled
epigenome profiling of clinical samples. With this advancement in technology, we
are now accumulating ATAC-seq samples from clinical samples at an unprecedented
rate. These epigenomic profiles hold the key to uncovering how transcriptional
programs are established in diverse human cells and are disrupted by genetic or
environmental factors. Thus, the barrier to deriving important clinical insights
from clinical epigenomic samples is no longer one of data generation but of data
analysis. Specifically, we are still missing easy-to-use software tools that
will enable non-computational scientists to analyze their own ATAC-seq samples.
To facilitate systematic pre-processing and management of ATAC-seq samples, we
developed an interactive, cross-platform, user-friendly and customized desktop
application: interactive-ATAC (I-ATAC). I-ATAC integrates command-line data
processing tools (FASTQC, Trimmomatic, BWA, Picard,
ATAC_BAM_shiftrt_gappedAlign.pl, Bedtools and Macs2) into an easy-to-use
platform with user interface to automatically pre-process ATAC-seq samples with
parallelized and customizable pipelines. Its performance has been tested using
public ATAC-seq datasets in GM12878 and CD4+T cells and a feature-based
comparison is performed with some available interactive LIMS (Galaxy, SMITH,
SeqBench, Wasp, NG6, openBIS). I-ATAC is designed to empower non-computational
scientists to process their own datasets and to break to exclusivity of data
analyses to computational scientists. Additionally, I-ATAC is capable of
processing WGS and ChIP-seq samples, and can be customized by the user for
one-independent or multiple-sequential operations.
DOI: 10.7717/peerj.4040
PMCID: PMC5702251
PMID: 29181276
Conflict of interest statement: The authors declare there are no competing
interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/31776829
|
1. Chromosome Res. 2020 Mar;28(1):69-85. doi: 10.1007/s10577-019-09619-9. Epub
2019 Nov 27.
Genomic methods in profiling DNA accessibility and factor localization.
Klein DC(1), Hainer SJ(2).
Author information:
(1)Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA,
15260, USA.
(2)Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA,
15260, USA. [email protected].
Recent advancements in next-generation sequencing technologies and accompanying
reductions in cost have led to an explosion of techniques to examine DNA
accessibility and protein localization on chromatin genome-wide. Generally,
accessible regions of chromatin are permissive for factor binding and are
therefore hotspots for regulation of gene expression; conversely, genomic
regions that are highly occupied by histone proteins are not permissive for
factor binding and are less likely to be active regulatory regions. Identifying
regions of differential accessibility can be useful to uncover putative gene
regulatory regions, such as enhancers, promoters, and insulators. In addition,
DNA-binding proteins, such as transcription factors that preferentially bind
certain DNA sequences and histone proteins that form the core of the nucleosome,
play essential roles in all DNA-templated processes. Determining the genomic
localization of chromatin-bound proteins is therefore essential in determining
functional roles, sequence motifs important for factor binding, and regulatory
networks controlling gene expression. In this review, we discuss techniques for
determining DNA accessibility and nucleosome positioning (DNase-seq, FAIRE-seq,
MNase-seq, and ATAC-seq) and techniques for detecting and functionally
characterizing chromatin-bound proteins (ChIP-seq, DamID, and CUT&RUN). These
methods have been optimized to varying degrees of resolution, specificity, and
ease of use. Here, we outline some advantages and disadvantages of these
techniques, their general protocols, and a brief discussion of their
development. Together, these complimentary approaches have provided an
unparalleled view of chromatin architecture and functional gene regulation.
DOI: 10.1007/s10577-019-09619-9
PMCID: PMC7125251
PMID: 31776829 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30078704
|
1. Cell. 2018 Aug 23;174(5):1309-1324.e18. doi: 10.1016/j.cell.2018.06.052. Epub
2018 Aug 2.
A Single-Cell Atlas of In Vivo Mammalian Chromatin Accessibility.
Cusanovich DA(1), Hill AJ(1), Aghamirzaie D(1), Daza RM(1), Pliner HA(1),
Berletch JB(2), Filippova GN(2), Huang X(3), Christiansen L(4), DeWitt WS(1),
Lee C(1), Regalado SG(1), Read DF(1), Steemers FJ(4), Disteche CM(2), Trapnell
C(5), Shendure J(6).
Author information:
(1)Department of Genome Sciences, University of Washington, Seattle, WA 98195,
USA.
(2)Department of Pathology, University of Washington, Seattle, WA 98195, USA.
(3)Department of Genome Sciences, University of Washington, Seattle, WA 98195,
USA; Department of Computer Science, University of Washington, Seattle, WA
98195, USA.
(4)Illumina, San Diego, CA 92122, USA.
(5)Department of Genome Sciences, University of Washington, Seattle, WA 98195,
USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
Electronic address: [email protected].
(6)Department of Genome Sciences, University of Washington, Seattle, WA 98195,
USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA;
Howard Hughes Medical Institute, Seattle, WA 98195, USA. Electronic address:
[email protected].
We applied a combinatorial indexing assay, sci-ATAC-seq, to profile genome-wide
chromatin accessibility in ∼100,000 single cells from 13 adult mouse tissues. We
identify 85 distinct patterns of chromatin accessibility, most of which can be
assigned to cell types, and ∼400,000 differentially accessible elements. We use
these data to link regulatory elements to their target genes, to define the
transcription factor grammar specifying each cell type, and to discover in vivo
correlates of heterogeneity in accessibility within cell types. We develop a
technique for mapping single cell gene expression data to single-cell chromatin
accessibility data, facilitating the comparison of atlases. By intersecting
mouse chromatin accessibility with human genome-wide association summary
statistics, we identify cell-type-specific enrichments of the heritability
signal for hundreds of complex traits. These data define the in vivo landscape
of the regulatory genome for common mammalian cell types at single-cell
resolution.
Copyright © 2018 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2018.06.052
PMCID: PMC6158300
PMID: 30078704 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29490630
|
1. BMC Genomics. 2018 Mar 1;19(1):169. doi: 10.1186/s12864-018-4559-3.
ATACseqQC: a Bioconductor package for post-alignment quality assessment of
ATAC-seq data.
Ou J(1), Liu H(2), Yu J(2), Kelliher MA(2), Castilla LH(2), Lawson ND(2), Zhu
LJ(3)(4).
Author information:
(1)Department of Cell Biology, Duke University Medical Center, Durham, NC,
27710, USA.
(2)Department of Molecular, Cell and Cancer Biology, University of Massachusetts
Medical School, 364 Plantation Street, Worcester, MA, 01605, USA.
(3)Department of Molecular, Cell and Cancer Biology, University of Massachusetts
Medical School, 364 Plantation Street, Worcester, MA, 01605, USA.
[email protected].
(4)Department of Molecular Medicine, Program in Bioinformatics and Integrative
Biology, Worcester, MA, 01655, USA. [email protected].
BACKGROUND: ATAC-seq (Assays for Transposase-Accessible Chromatin using
sequencing) is a recently developed technique for genome-wide analysis of
chromatin accessibility. Compared to earlier methods for assaying chromatin
accessibility, ATAC-seq is faster and easier to perform, does not require
cross-linking, has higher signal to noise ratio, and can be performed on small
cell numbers. However, to ensure a successful ATAC-seq experiment, step-by-step
quality assurance processes, including both wet lab quality control and in
silico quality assessment, are essential. While several tools have been
developed or adopted for assessing read quality, identifying nucleosome
occupancy and accessible regions from ATAC-seq data, none of the tools provide a
comprehensive set of functionalities for preprocessing and quality assessment of
aligned ATAC-seq datasets.
RESULTS: We have developed a Bioconductor package, ATACseqQC, for easily
generating various diagnostic plots to help researchers quickly assess the
quality of their ATAC-seq data. In addition, this package contains functions to
preprocess aligned ATAC-seq data for subsequent peak calling. Here we
demonstrate the utilities of our package using 25 publicly available ATAC-seq
datasets from four studies. We also provide guidelines on what the diagnostic
plots should look like for an ideal ATAC-seq dataset.
CONCLUSIONS: This software package has been used successfully for preprocessing
and assessing several in-house and public ATAC-seq datasets. Diagnostic plots
generated by this package will facilitate the quality assessment of ATAC-seq
data, and help researchers to evaluate their own ATAC-seq experiments as well as
select high-quality ATAC-seq datasets from public repositories such as GEO to
avoid generating hypotheses or drawing conclusions from low-quality ATAC-seq
experiments. The software, source code, and documentation are freely available
as a Bioconductor package at
https://bioconductor.org/packages/release/bioc/html/ATACseqQC.html .
DOI: 10.1186/s12864-018-4559-3
PMCID: PMC5831847
PMID: 29490630 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The
authors declare that they have no competing interests. PUBLISHER’S NOTE:
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
|
http://www.ncbi.nlm.nih.gov/pubmed/25559105
|
1. Curr Protoc Mol Biol. 2015 Jan 5;109:21.29.1-21.29.9. doi:
10.1002/0471142727.mb2129s109.
ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide.
Buenrostro JD(1)(2), Wu B(1), Chang HY(2), Greenleaf WJ(1).
Author information:
(1)Department of Genetics, Stanford University School of Medicine, Stanford,
California.
(2)Program in Epithelial Biology and the Howard Hughes Medical Institute,
Stanford University School of Medicine, Stanford, California.
This unit describes Assay for Transposase-Accessible Chromatin with
high-throughput sequencing (ATAC-seq), a method for mapping chromatin
accessibility genome-wide. This method probes DNA accessibility with hyperactive
Tn5 transposase, which inserts sequencing adapters into accessible regions of
chromatin. Sequencing reads can then be used to infer regions of increased
accessibility, as well as to map regions of transcription-factor binding and
nucleosome position. The method is a fast and sensitive alternative to DNase-seq
for assaying chromatin accessibility genome-wide, or to MNase-seq for assaying
nucleosome positions in accessible regions of the genome.
Copyright © 2015 John Wiley & Sons, Inc.
DOI: 10.1002/0471142727.mb2129s109
PMCID: PMC4374986
PMID: 25559105 [Indexed for MEDLINE]
Conflict of interest statement: Competing financial interests Stanford
University has filed a provisional patent application on the methods described,
and J.D.B., H.Y.C. and W.J.G. are named as inventors.
|
http://www.ncbi.nlm.nih.gov/pubmed/27008018
|
1. Methods Mol Biol. 2016;1418:225-40. doi: 10.1007/978-1-4939-3578-9_12.
Genome-Scale Analysis of Cell-Specific Regulatory Codes Using Nuclear Enzymes.
Baek S(1), Sung MH(2)(3).
Author information:
(1)Laboratory of Receptor Biology and Gene Expression, National Cancer
Institute, National Institutes of Health, 41 Library Drive, Bethesda, MD, 20892,
USA.
(2)Laboratory of Receptor Biology and Gene Expression, National Cancer
Institute, National Institutes of Health, 41 Library Drive, Bethesda, MD, 20892,
USA. [email protected].
(3)Laboratory of Molecular Biology and Immunology, National Institute on Aging,
National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
[email protected].
High-throughput sequencing technologies have made it possible for biologists to
generate genome-wide profiles of chromatin features at the nucleotide
resolution. Enzymes such as nucleases or transposes have been instrumental as a
chromatin-probing agent due to their ability to target accessible chromatin for
cleavage or insertion. On the scale of a few hundred base pairs, preferential
action of the nuclear enzymes on accessible chromatin allows mapping of cell
state-specific accessibility in vivo. Such accessible regions contain
functionally important regulatory sites, including promoters and enhancers,
which undergo active remodeling for cells adapting in a dynamic environment.
DNase-seq and the more recent ATAC-seq are two assays that are gaining
popularity. Deep sequencing of DNA libraries from these assays, termed genomic
footprinting, has been proposed to enable the comprehensive construction of
protein occupancy profiles over the genome at the nucleotide level. Recent
studies have discovered limitations of genomic footprinting which reduce the
scope of detectable proteins. In addition, the identification of putative
factors that bind to the observed footprints remains challenging. Despite these
caveats, the methodology still presents significant advantages over alternative
techniques such as ChIP-seq or FAIRE-seq. Here we describe computational
approaches and tools for analysis of chromatin accessibility and genomic
footprinting. Proper experimental design and assay-specific data analysis ensure
the detection sensitivity and maximize retrievable information. The enzyme-based
chromatin profiling approaches represent a powerful and evolving methodology
which facilitates our understanding of how the genome is regulated.
DOI: 10.1007/978-1-4939-3578-9_12
PMCID: PMC5142241
PMID: 27008018 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/28967996
|
1. Curr Protoc Mol Biol. 2017 Oct 2;120:21.34.1-21.34.18. doi: 10.1002/cpmb.45.
Single-Assay Profiling of Nucleosome Occupancy and Chromatin Accessibility.
Cook A(1)(2), Mieczkowski J(1)(3), Tolstorukov MY(1).
Author information:
(1)Department of Molecular Biology, Massachusetts General Hospital and Harvard
Medical School, Boston, Massachusetts.
(2)Current address: Dana-Farber Cancer Institute, Boston, Massachusetts.
(3)Current address: Neurobiology Center, Nencki Institute of Experimental
Biology, Warsaw, Poland.
This unit describes a method for determining the accessibility of chromatinized
DNA and nucleosome occupancy in the same assay. Enzymatic digestion of chromatin
using micrococcal nuclease (MNase) is optimized for liberation, retrieval, and
characterization of DNA fragments from chromatin. MNase digestion is performed
in a titration series, and the DNA fragments are isolated and sequenced for each
individual digest independently. These sequenced fragments are then collectively
analyzed in a novel bioinformatics pipeline to produce a metric describing MNase
accessibility of chromatin (MACC) and nucleosome occupancy. This approach allows
profiling of the entire genome including regions of open and closed chromatin.
Moreover, the MACC protocol can be supplemented with a histone
immunoprecipitation step to estimate and compare both histone and non-histone
DNA protection components. © 2017 by John Wiley & Sons, Inc.
Copyright © 2017 John Wiley and Sons, Inc.
DOI: 10.1002/cpmb.45
PMID: 28967996 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30948010
|
1. Methods Cell Biol. 2019;151:219-235. doi: 10.1016/bs.mcb.2018.11.002. Epub
2018 Dec 21.
Genome-wide analysis of chromatin accessibility using ATAC-seq.
Shashikant T(1), Ettensohn CA(2).
Author information:
(1)Department of Biological Sciences, Carnegie Mellon University, Pittsburgh,
PA, United States.
(2)Department of Biological Sciences, Carnegie Mellon University, Pittsburgh,
PA, United States. Electronic address: [email protected].
Programs of gene transcription are controlled by cis-acting DNA elements,
including enhancers, silencers, and promoters. Local accessibility of chromatin
has proven to be a highly informative structural feature for identifying such
regulatory elements, which tend to be relatively open due to their interactions
with proteins. Recently, ATAC-seq (assay for transposase-accessible chromatin
using sequencing) has emerged as one of the most powerful approaches for
genome-wide chromatin accessibility profiling. This method assesses DNA
accessibility using hyperactive Tn5 transposase, which simultaneously cuts DNA
and inserts sequencing adaptors, preferentially in regions of open chromatin.
ATAC-seq is a relatively simple procedure which can be applied to only a few
thousand cells. It is well-suited to developing embryos of sea urchins and other
echinoderms, which are a prominent experimental model for understanding the
genomic control of animal development. In this chapter, we present a protocol
for applying ATAC-seq to embryonic cells of sea urchins.
© 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/bs.mcb.2018.11.002
PMCID: PMC7259819
PMID: 30948010 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34255854
|
1. Nucleic Acids Res. 2021 Aug 20;49(14):7925-7938. doi: 10.1093/nar/gkab553.
RoboCOP: jointly computing chromatin occupancy profiles for numerous factors
from chromatin accessibility data.
Mitra S(1), Zhong J(2), Tran TQ(1), MacAlpine DM(2)(3)(4), Hartemink
AJ(1)(2)(4).
Author information:
(1)Department of Computer Science, Duke University, Durham, NC 27708, USA.
(2)Program in Computational Biology and Bioinformatics, Duke University, Durham,
NC 27708, USA.
(3)Department of Pharmacology and Cancer Biology, Duke University Medical
Center, Durham, NC 27710, USA.
(4)Center for Genomic and Computational Biology, Duke University, Durham, NC
27708, USA.
Chromatin is a tightly packaged structure of DNA and protein within the nucleus
of a cell. The arrangement of different protein complexes along the DNA
modulates and is modulated by gene expression. Measuring the binding locations
and occupancy levels of different transcription factors (TFs) and nucleosomes is
therefore crucial to understanding gene regulation. Antibody-based methods for
assaying chromatin occupancy are capable of identifying the binding sites of
specific DNA binding factors, but only one factor at a time. In contrast,
epigenomic accessibility data like MNase-seq, DNase-seq, and ATAC-seq provide
insight into the chromatin landscape of all factors bound along the genome, but
with little insight into the identities of those factors. Here, we present
RoboCOP, a multivariate state space model that integrates chromatin
accessibility data with nucleotide sequence to jointly compute genome-wide
probabilistic scores of nucleosome and TF occupancy, for hundreds of different
factors. We apply RoboCOP to MNase-seq and ATAC-seq data to elucidate the
protein-binding landscape of nucleosomes and 150 TFs across the yeast genome,
and show that our model makes better predictions than existing methods. We also
compute a chromatin occupancy profile of the yeast genome under cadmium stress,
revealing chromatin dynamics associated with transcriptional regulation.
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkab553
PMCID: PMC8373080
PMID: 34255854 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33606259
|
1. Methods Mol Biol. 2021;2243:183-226. doi: 10.1007/978-1-0716-1103-6_10.
Interrogating the Accessible Chromatin Landscape of Eukaryote Genomes Using
ATAC-seq.
Marinov GK(1), Shipony Z(2).
Author information:
(1)Department of Genetics, Stanford University, Stanford, CA, USA.
(2)Department of Genetics, Stanford University, Stanford, CA, USA.
[email protected].
The ATAC-seq assay has emerged as the most useful, versatile, and widely
adaptable method for profiling accessible chromatin regions and tracking the
activity of cis-regulatory elements (cREs) in eukaryotes. Thanks to its great
utility, it is now being applied to map active chromatin in the context of a
very wide diversity of biological systems and questions. In the course of these
studies, considerable experience working with ATAC-seq data has accumulated and
a standard set of computational tasks that need to be carried for most ATAC-seq
analyses has emerged. Here, we review and provide examples of common such
analytical procedures (including data processing, quality control, peak calling,
identifying differentially accessible open chromatin regions, and variable
transcription factor (TF) motif accessibility) and discuss recommended optimal
practices.
DOI: 10.1007/978-1-0716-1103-6_10
PMID: 33606259 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33693880
|
1. Nucleic Acids Res. 2021 Jun 4;49(10):e56. doi: 10.1093/nar/gkab102.
Multiplex indexing approach for the detection of DNase I hypersensitive sites in
single cells.
Gao W(1)(2)(3), Ku WL(1), Pan L(1), Perrie J(1), Zhao T(4), Hu G(1), Wu Y(2),
Zhu J(1), Ni B(2)(3), Zhao K(1).
Author information:
(1)Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung
and Blood Institute, NIH, Bethesda, MD, USA.
(2)Institute of Immunology of PLA, Third Military Medical University, Chongqing
400038, PR China.
(3)Department of Pathophysiology, College of High Altitude Military Medicine,
Third Military Medical University, Chongqing 400038, PR China.
(4)Chongqing International Institute for Immunology, Chongqing 401338, PR China.
Single cell chromatin accessibility assays reveal epigenomic variability at
cis-regulatory elements among individual cells. We previously developed a
single-cell DNase-seq assay (scDNase-seq) to profile accessible chromatin in a
limited number of single cells. Here, we report a novel indexing strategy to
resolve single-cell DNase hypersensitivity profiles based on bulk cell analysis.
This new technique, termed indexing single-cell DNase sequencing (iscDNase-seq),
employs the activities of terminal DNA transferase (TdT) and T4 DNA ligase to
add unique cell barcodes to DNase-digested chromatin ends. By a three-layer
indexing strategy, it allows profiling genome-wide DHSs for >15 000 single-cells
in a single experiment. Application of iscDNase-seq to human white blood cells
accurately revealed specific cell types and inferred regulatory transcription
factors (TF) specific to each cell type. We found that iscDNase-seq detected
DHSs with specific properties related to gene expression and conservation missed
by scATAC-seq for the same cell type. Also, we found that the cell-to-cell
variation in accessibility computed using iscDNase-seq data is significantly
correlated with the cell-to-cell variation in gene expression. Importantly, this
correlation is significantly higher than that between scATAC-seq and scRNA-seq,
suggesting that iscDNase-seq data can better predict the cellular heterogeneity
in gene expression compared to scATAC-seq. Thus, iscDNase-seq is an attractive
alternative method for single-cell epigenomics studies.
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkab102
PMCID: PMC8191781
PMID: 33693880 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32312702
|
1. Yi Chuan. 2020 Apr 20;42(4):333-346. doi: 10.16288/j.yczz.19-279.
[Advances in assay for transposase-accessible chromatin with high-throughput
sequencing].
[Article in Chinese; Abstract available in Chinese from the publisher]
Wu J(1), Quan JP(1), Ye Y(1), Wu ZF(1), Yang J(1), Yang M(2), Zheng EQ(1).
Author information:
(1)National Engineering Research Center for Breeding Swine Industry, College of
Animal Science, South China Agricultural University, Guangzhou 510642, China.
(2)College of Animal Science and Technology, Zhongkai University of Agriculture
and Engineering, Guangzhou 510225, China.
Assay for transposase accessible chromatin with high-throughput sequencing
(ATAC-seq) was developed in 2013. It has the advantages of more convenient
operation and higher efficiency for DNA recovery than DNase I hypersensitive
site sequencing (DNase-seq) and micrococcal nuclease sequencing (MNase-seq).
ATAC-seq currently is the most popular technique of genome-wide mapping for
chromatin accessibility. It provides information on binding regions of
transcription factors and nucleosome localization on the chromatin. Thus,
ATAC-seq is of great significance for studying the epigenetics and molecular
mechanisms in chromatin structure. In this review, we compare the advantages and
disadvantages of multiple techniques for profiling chromatin accessibility, and
summarize the principles, main process, development and applications of
ATAC-seq. We hope this review will provide a reference for study of genome-wide
mapping for chromatin accessibility, identification of cis-regulatory elements,
and dissection of the epigenetic and genetic regulatory networks using the
ATAC-seq technology in eukaryotes.
Publisher: 染色质转座酶可及性测序(assay for transposase-accessible chromatin with
high-throughput sequencing,
ATAC-seq)诞生于2013年,具有比脱氧核糖核酸酶I超敏感位点测序(deoxyribonuclease I hypersensitive site
sequencing, DNase-seq)和微球菌核酸酶敏感位点测序(micrococcal nuclease sequencing,
MNase-seq)更快速、灵敏、简便的优点,是目前分析全基因组范围染色质开放区域的热点技术。通过该技术能获得染色质开放区域的相关信息,从而映射出转录因子等调控蛋白的结合区域和核小体定位等信息,对于研究表观遗传分子机制具有重要意义。本文比较了5种获取染色质开放区域技术的优缺点,重点介绍了ATAC-seq的原理和主要流程,描述了利用ATAC-seq技术研究染色质开放区域的发展概况以及ATAC-seq的相关应用,期望对真核生物全基因组水平的染色质开放区域研究、顺式调控元件鉴定以及遗传调控网络的解析等提供借鉴。.
DOI: 10.16288/j.yczz.19-279
PMID: 32312702 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33584814
|
1. Front Genet. 2021 Jan 13;11:618478. doi: 10.3389/fgene.2020.618478.
eCollection 2020.
ATACgraph: Profiling Genome-Wide Chromatin Accessibility From ATAC-seq.
Lu RJ(1)(2), Liu YT(1), Huang CW(3), Yen MR(1), Lin CY(3), Chen PY(1).
Author information:
(1)Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan.
(2)Department of Medicine, Washington University in St. Louis, St. Louis, MO,
United States.
(3)Institute of Information Science, Academia Sinica, Taipei, Taiwan.
Assay for transposase-accessible chromatin using sequencing data (ATAC-seq) is
an efficient and precise method for revealing chromatin accessibility across the
genome. Most of the current ATAC-seq tools follow chromatin immunoprecipitation
sequencing (ChIP-seq) strategies that do not consider ATAC-seq-specific
properties. To incorporate specific ATAC-seq quality control and the underlying
biology of chromatin accessibility, we developed a bioinformatics software named
ATACgraph for analyzing and visualizing ATAC-seq data. ATACgraph profiles
accessible chromatin regions and provides ATAC-seq-specific information
including definitions of nucleosome-free regions (NFRs) and nucleosome-occupied
regions. ATACgraph also allows identification of differentially accessible
regions between two ATAC-seq datasets. ATACgraph incorporates the docker image
with the Galaxy platform to provide an intuitive user experience via the
graphical interface. Without tedious installation processes on a local machine
or cloud, users can analyze data through activated websites using pre-designed
workflows or customized pipelines composed of ATACgraph modules. Overall,
ATACgraph is an effective tool designed for ATAC-seq for biologists with minimal
bioinformatics knowledge to analyze chromatin accessibility. ATACgraph can be
run on any ATAC-seq data with no limit to specific genomes. As validation, we
demonstrated ATACgraph on human genome to showcase its functions for ATAC-seq
interpretation. This software is publicly accessible and can be downloaded at
https://github.com/RitataLU/ATACgraph.
Copyright © 2021 Lu, Liu, Huang, Yen, Lin and Chen.
DOI: 10.3389/fgene.2020.618478
PMCID: PMC7874078
PMID: 33584814
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/32042188
|
1. Nat Methods. 2020 Mar;17(3):319-327. doi: 10.1038/s41592-019-0730-2. Epub 2020
Feb 10.
Long-range single-molecule mapping of chromatin accessibility in eukaryotes.
Shipony Z(#)(1), Marinov GK(#)(1), Swaffer MP(2), Sinnott-Armstrong NA(1),
Skotheim JM(2), Kundaje A(1)(3), Greenleaf WJ(4)(5)(6).
Author information:
(1)Department of Genetics, Stanford University, Stanford, CA, USA.
(2)Department of Biology, Stanford University, Stanford, CA, USA.
(3)Department of Computer Science, Stanford University, Stanford, CA, USA.
(4)Department of Genetics, Stanford University, Stanford, CA, USA.
[email protected].
(5)Department of Applied Physics, Stanford University, Stanford, CA, USA.
[email protected].
(6)Chan Zuckerberg Biohub, San Francisco, CA, USA. [email protected].
(#)Contributed equally
Mapping open chromatin regions has emerged as a widely used tool for identifying
active regulatory elements in eukaryotes. However, existing approaches, limited
by reliance on DNA fragmentation and short-read sequencing, cannot provide
information about large-scale chromatin states or reveal coordination between
the states of distal regulatory elements. We have developed a method for
profiling the accessibility of individual chromatin fibers, a single-molecule
long-read accessible chromatin mapping sequencing assay (SMAC-seq), enabling the
simultaneous, high-resolution, single-molecule assessment of chromatin states at
multikilobase length scales. Our strategy is based on combining the preferential
methylation of open chromatin regions by DNA methyltransferases with low
sequence specificity, in this case EcoGII, an N6-methyladenosine (m6A)
methyltransferase, and the ability of nanopore sequencing to directly read DNA
modifications. We demonstrate that aggregate SMAC-seq signals match bulk-level
accessibility measurements, observe single-molecule nucleosome and transcription
factor protection footprints, and quantify the correlation between chromatin
states of distal genomic elements.
DOI: 10.1038/s41592-019-0730-2
PMCID: PMC7968351
PMID: 32042188 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26846207
|
1. Genome Biol. 2016 Feb 4;17:20. doi: 10.1186/s13059-016-0882-7.
Characterization of chromatin accessibility with a transposome hypersensitive
sites sequencing (THS-seq) assay.
Sos BC(1)(2), Fung HL(1), Gao DR(1), Osothprarop TF(3), Kia A(3), He MM(3),
Zhang K(4)(5).
Author information:
(1)Department of Bioengineering, University of California San Diego, 9500 Gilman
Drive, La Jolla, CA, USA.
(2)Biomedical Sciences Graduate Program, University of California San Diego,
9500 Gilman Drive, La Jolla, CA, USA.
(3)Illumina Inc, 5200 Illumina Way, San Diego, CA, USA.
(4)Department of Bioengineering, University of California San Diego, 9500 Gilman
Drive, La Jolla, CA, USA. [email protected].
(5)Biomedical Sciences Graduate Program, University of California San Diego,
9500 Gilman Drive, La Jolla, CA, USA. [email protected].
Chromatin accessibility captures in vivo protein-chromosome binding status, and
is considered an informative proxy for protein-DNA interactions. DNase I and Tn5
transposase assays require thousands to millions of fresh cells for
comprehensive chromatin mapping. Applying Tn5 tagmentation to hundreds of cells
results in sparse chromatin maps. We present a transposome hypersensitive sites
sequencing assay for highly sensitive characterization of chromatin
accessibility. Linear amplification of accessible DNA ends with in vitro
transcription, coupled with an engineered Tn5 super-mutant, demonstrates
improved sensitivity on limited input materials, and accessibility of small
regions near distal enhancers, compared with ATAC-seq.
DOI: 10.1186/s13059-016-0882-7
PMCID: PMC4743176
PMID: 26846207 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34382186
|
1. Methods Mol Biol. 2021;2351:105-121. doi: 10.1007/978-1-0716-1597-3_6.
Measuring Chromatin Accessibility: ATAC-Seq.
Sahu SK(#)(1), Basu A(#)(2), Tiwari VK(3).
Author information:
(1)Salk Institute for Biological Studies, La Jolla, CA, USA.
(2)Institute of Molecular Biology (IMB), Mainz, Germany.
(3)Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine,
Dentistry & Biomedical Science, Queen's University Belfast, Belfast, UK.
[email protected].
(#)Contributed equally
Assay for Transposase-Accessible Chromatin using sequencing (ATAC-Seq) is a
method to investigate the accessibility of chromatin in a genome-wide fashion.
In this chapter, we provide a brief history of the chromatin accessibility field
followed by a detailed protocol to perform ATAC-Seq assay.
© 2021. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-1597-3_6
PMID: 34382186 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35478247
|
1. Nat Protoc. 2022 Jun;17(6):1518-1552. doi: 10.1038/s41596-022-00692-9. Epub
2022 Apr 27.
Chromatin accessibility profiling by ATAC-seq.
Grandi FC(1)(2)(3), Modi H(1)(2)(3), Kampman L(1)(2)(3), Corces MR(4)(5)(6).
Author information:
(1)Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
(2)Gladstone Institute of Data Science and Biotechnology, San Francisco, CA,
USA.
(3)Department of Neurology, University of California San Francisco, San
Francisco, CA, USA.
(4)Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
[email protected].
(5)Gladstone Institute of Data Science and Biotechnology, San Francisco, CA,
USA. [email protected].
(6)Department of Neurology, University of California San Francisco, San
Francisco, CA, USA. [email protected].
The assay for transposase-accessible chromatin using sequencing (ATAC-seq)
provides a simple and scalable way to detect the unique chromatin landscape
associated with a cell type and how it may be altered by perturbation or
disease. ATAC-seq requires a relatively small number of input cells and does not
require a priori knowledge of the epigenetic marks or transcription factors
governing the dynamics of the system. Here we describe an updated and optimized
protocol for ATAC-seq, called Omni-ATAC, that is applicable across a broad range
of cell and tissue types. The ATAC-seq workflow has five main steps: sample
preparation, transposition, library preparation, sequencing and data analysis.
This protocol details the steps to generate and sequence ATAC-seq libraries,
with recommendations for sample preparation and downstream bioinformatic
analysis. ATAC-seq libraries for roughly 12 samples can be generated in 10 h by
someone familiar with basic molecular biology, and downstream sequencing
analysis can be implemented using benchmarked pipelines by someone with basic
bioinformatics skills and with access to a high-performance computing
environment.
© 2022. Springer Nature Limited.
DOI: 10.1038/s41596-022-00692-9
PMCID: PMC9189070
PMID: 35478247 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/27993786
|
1. Bioinformatics. 2017 Apr 1;33(7):956-963. doi: 10.1093/bioinformatics/btw740.
DeFCoM: analysis and modeling of transcription factor binding sites using a
motif-centric genomic footprinter.
Quach B(1)(2)(3), Furey TS(2)(3).
Author information:
(1)Curriculum in Bioinformatics and Computational Biology.
(2)Department of Genetics.
(3)Department of Biology, University of North Carolina, Chapel Hill, NC 27599,
USA.
MOTIVATION: Identifying the locations of transcription factor binding sites is
critical for understanding how gene transcription is regulated across different
cell types and conditions. Chromatin accessibility experiments such as DNaseI
sequencing (DNase-seq) and Assay for Transposase Accessible Chromatin sequencing
(ATAC-seq) produce genome-wide data that include distinct 'footprint' patterns
at binding sites. Nearly all existing computational methods to detect footprints
from these data assume that footprint signals are highly homogeneous across
footprint sites. Additionally, a comprehensive and systematic comparison of
footprinting methods for specifically identifying which motif sites for a
specific factor are bound has not been performed.
RESULTS: Using DNase-seq data from the ENCODE project, we show that a large
degree of previously uncharacterized site-to-site variability exists in
footprint signal across motif sites for a transcription factor. To model this
heterogeneity in the data, we introduce a novel, supervised learning footprinter
called Detecting Footprints Containing Motifs (DeFCoM). We compare DeFCoM to
nine existing methods using evaluation sets from four human cell-lines and
eighteen transcription factors and show that DeFCoM outperforms current methods
in determining bound and unbound motif sites. We also analyze the impact of
several biological and technical factors on the quality of footprint predictions
to highlight important considerations when conducting footprint analyses and
assessing the performance of footprint prediction methods. Finally, we show that
DeFCoM can detect footprints using ATAC-seq data with similar accuracy as when
using DNase-seq data.
AVAILABILITY AND IMPLEMENTATION: Python code available at
https://bitbucket.org/bryancquach/defcom.
CONTACT: [email protected] or [email protected].
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
© The Author 2016. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected]
DOI: 10.1093/bioinformatics/btw740
PMCID: PMC6075477
PMID: 27993786 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24992477
|
1. PLoS Genet. 2014 Jul 3;10(7):e1004427. doi: 10.1371/journal.pgen.1004427.
eCollection 2014 Jul.
Evolution and genetic architecture of chromatin accessibility and function in
yeast.
Connelly CF(1), Wakefield J(2), Akey JM(1).
Author information:
(1)Department of Genome Sciences, University of Washington, Seattle, Washington,
United States of America.
(2)Department of Statistics, University of Washington, Seattle, Washington,
United States of America.
Chromatin accessibility is an important functional genomics phenotype that
influences transcription factor binding and gene expression. Genome-scale
technologies allow chromatin accessibility to be mapped with high-resolution,
facilitating detailed analyses into the genetic architecture and evolution of
chromatin structure within and between species. We performed
Formaldehyde-Assisted Isolation of Regulatory Elements sequencing (FAIRE-Seq) to
map chromatin accessibility in two parental haploid yeast species, Saccharomyces
cerevisiae and Saccharomyces paradoxus and their diploid hybrid. We show that
although broad-scale characteristics of the chromatin landscape are well
conserved between these species, accessibility is significantly different for
947 regions upstream of genes that are enriched for GO terms such as
intracellular transport and protein localization exhibit. We also develop new
statistical methods to investigate the genetic architecture of variation in
chromatin accessibility between species, and find that cis effects are more
common and of greater magnitude than trans effects. Interestingly, we find that
cis and trans effects at individual genes are often negatively correlated,
suggesting widespread compensatory evolution to stabilize levels of chromatin
accessibility. Finally, we demonstrate that the relationship between chromatin
accessibility and gene expression levels is complex, and a significant
proportion of differences in chromatin accessibility might be functionally
benign.
DOI: 10.1371/journal.pgen.1004427
PMCID: PMC4081003
PMID: 24992477 [Indexed for MEDLINE]
Conflict of interest statement: JMA is a paid consultant of Glenview Capital.
|
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