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Cell_Biology_Alberts_910	Cell_Biology_Alberts	In genetic engineering experiments, the HS4 sequence is often added to both ends of a gene that is to be inserted into a mammalian genome, in order to protect that gene from the silencing caused by spreading heterochromatin. Analysis of this barrier sequence reveals that it contains a cluster of binding sites for histone acetylase enzymes. Since the acetylation of a lysine side chain is incompatible with the methylation of the same side chain, and specific lysine methylations are required to spread heterochromatin, histone acetylases are logical candidates for the formation of DNA barriers to spreading (Figure 4–41). However, several other types of chromatin modifications are known that can also protect genes from silencing. Figure 4–41 Some mechanisms of barrier action. These models are derived from experimental analyses of barrier action, and a combination of several of them may function at any one site.	Cell_Biology_Alberts. In genetic engineering experiments, the HS4 sequence is often added to both ends of a gene that is to be inserted into a mammalian genome, in order to protect that gene from the silencing caused by spreading heterochromatin. Analysis of this barrier sequence reveals that it contains a cluster of binding sites for histone acetylase enzymes. Since the acetylation of a lysine side chain is incompatible with the methylation of the same side chain, and specific lysine methylations are required to spread heterochromatin, histone acetylases are logical candidates for the formation of DNA barriers to spreading (Figure 4–41). However, several other types of chromatin modifications are known that can also protect genes from silencing. Figure 4–41 Some mechanisms of barrier action. These models are derived from experimental analyses of barrier action, and a combination of several of them may function at any one site.
Cell_Biology_Alberts_911	Cell_Biology_Alberts	Figure 4–41 Some mechanisms of barrier action. These models are derived from experimental analyses of barrier action, and a combination of several of them may function at any one site. The tethering of a region of chromatin to a large fixed site, such as the nuclear pore complex illustrated here, can form a barrier that stops the spread of heterochromatin. The tight binding of barrier proteins to a group of nucleosomes can make this chromatin resistant to heterochromatin spreading. (C) by recruiting a group of highly active histone-modifying enzymes, barriers can erase the histone marks that are required for heterochromatin to spread. For example, a potent acetylation of lysine 9 on histone H3 will compete with lysine 9 methylation, thereby preventing the binding of the HP1 protein needed to form a major form of heterochromatin. (based on A.g. west and P. Fraser, Hum. Mol. Genet. 14:R101–R111, 2005. with permission from Oxford University Press.)	Cell_Biology_Alberts. Figure 4–41 Some mechanisms of barrier action. These models are derived from experimental analyses of barrier action, and a combination of several of them may function at any one site. The tethering of a region of chromatin to a large fixed site, such as the nuclear pore complex illustrated here, can form a barrier that stops the spread of heterochromatin. The tight binding of barrier proteins to a group of nucleosomes can make this chromatin resistant to heterochromatin spreading. (C) by recruiting a group of highly active histone-modifying enzymes, barriers can erase the histone marks that are required for heterochromatin to spread. For example, a potent acetylation of lysine 9 on histone H3 will compete with lysine 9 methylation, thereby preventing the binding of the HP1 protein needed to form a major form of heterochromatin. (based on A.g. west and P. Fraser, Hum. Mol. Genet. 14:R101–R111, 2005. with permission from Oxford University Press.)
Cell_Biology_Alberts_912	Cell_Biology_Alberts	A.g. west and P. Fraser, Hum. Mol. Genet. 14:R101–R111, 2005. with permission from Oxford University Press.) The Chromatin in Centromeres Reveals How Histone variants Can Create Special Structures	Cell_Biology_Alberts. A.g. west and P. Fraser, Hum. Mol. Genet. 14:R101–R111, 2005. with permission from Oxford University Press.) The Chromatin in Centromeres Reveals How Histone variants Can Create Special Structures
Cell_Biology_Alberts_913	Cell_Biology_Alberts	Nucleosomes carrying histone variants have a distinctive character and are thought to be able to produce marks in chromatin that are unusually long-lasting. An important example is seen in the formation and inheritance of the specialized chromatin structure at the centromere, the region of each chromosome required for attachment to the mitotic spindle and orderly segregation of the duplicated copies of the genome into daughter cells each time a cell divides. In many complex organisms, including humans, each centromere is embedded in a stretch of special centromeric chromatin that persists throughout interphase, even though the centromere-mediated attachment to the spindle and movement of DNA occur only during mitosis. This chromatin contains a centromere-specific variant H3 histone, known as CENP-A (Centromere Protein-A; see Figure 4–35), plus additional proteins that pack the nucleosomes into particularly dense arrangements and form the kinetochore, the special structure required for	Cell_Biology_Alberts. Nucleosomes carrying histone variants have a distinctive character and are thought to be able to produce marks in chromatin that are unusually long-lasting. An important example is seen in the formation and inheritance of the specialized chromatin structure at the centromere, the region of each chromosome required for attachment to the mitotic spindle and orderly segregation of the duplicated copies of the genome into daughter cells each time a cell divides. In many complex organisms, including humans, each centromere is embedded in a stretch of special centromeric chromatin that persists throughout interphase, even though the centromere-mediated attachment to the spindle and movement of DNA occur only during mitosis. This chromatin contains a centromere-specific variant H3 histone, known as CENP-A (Centromere Protein-A; see Figure 4–35), plus additional proteins that pack the nucleosomes into particularly dense arrangements and form the kinetochore, the special structure required for
Cell_Biology_Alberts_914	Cell_Biology_Alberts	as CENP-A (Centromere Protein-A; see Figure 4–35), plus additional proteins that pack the nucleosomes into particularly dense arrangements and form the kinetochore, the special structure required for attachment of the mitotic spindle (see Figure 4–19).	Cell_Biology_Alberts. as CENP-A (Centromere Protein-A; see Figure 4–35), plus additional proteins that pack the nucleosomes into particularly dense arrangements and form the kinetochore, the special structure required for attachment of the mitotic spindle (see Figure 4–19).
Cell_Biology_Alberts_915	Cell_Biology_Alberts	A specific DNA sequence of approximately 125 nucleotide pairs is sufficient to serve as a centromere in the yeast S. cerevisiae. Despite its small size, more than a dozen different proteins assemble on this DNA sequence; the proteins include the CENP-A histone H3 variant, which, along with the three other core histones, forms a centromere-specific nucleosome. The additional proteins at the yeast centromere attach this nucleosome to a single microtubule from the yeast mitotic spindle (Figure 4–42).	Cell_Biology_Alberts. A specific DNA sequence of approximately 125 nucleotide pairs is sufficient to serve as a centromere in the yeast S. cerevisiae. Despite its small size, more than a dozen different proteins assemble on this DNA sequence; the proteins include the CENP-A histone H3 variant, which, along with the three other core histones, forms a centromere-specific nucleosome. The additional proteins at the yeast centromere attach this nucleosome to a single microtubule from the yeast mitotic spindle (Figure 4–42).
Cell_Biology_Alberts_916	Cell_Biology_Alberts	The centromeres in more complex organisms are considerably larger than those in budding yeasts. For example, fly and human centromeres extend over hundreds of thousands of nucleotide pairs and, while they contain CENP-A, they do not seem to contain a centromere-specific DNA sequence. These centromeres largely consist of short, repeated DNA sequences, known as alpha satellite DNA in humans. But the same repeat sequences are also found at other (non-centromeric) positions on chromosomes, indicating that they are not sufficient to direct centromere formation. Most strikingly, in some unusual cases, new human centromeres (called neocentromeres) have been observed to form spontaneously on fragmented chromosomes. Some of these new positions were originally euchromatic and lack alpha satellite DNA altogether (Figure 4–43). It seems that centromeres in complex organisms are defined by an assembly of proteins, rather than by a specific DNA sequence.	Cell_Biology_Alberts. The centromeres in more complex organisms are considerably larger than those in budding yeasts. For example, fly and human centromeres extend over hundreds of thousands of nucleotide pairs and, while they contain CENP-A, they do not seem to contain a centromere-specific DNA sequence. These centromeres largely consist of short, repeated DNA sequences, known as alpha satellite DNA in humans. But the same repeat sequences are also found at other (non-centromeric) positions on chromosomes, indicating that they are not sufficient to direct centromere formation. Most strikingly, in some unusual cases, new human centromeres (called neocentromeres) have been observed to form spontaneously on fragmented chromosomes. Some of these new positions were originally euchromatic and lack alpha satellite DNA altogether (Figure 4–43). It seems that centromeres in complex organisms are defined by an assembly of proteins, rather than by a specific DNA sequence.
Cell_Biology_Alberts_917	Cell_Biology_Alberts	Inactivation of some centromeres and genesis of others de novo seem to have played an essential part in evolution. Different species, even when quite closely Figure 4–42 A model for the structure of a simple centromere. (A) In the yeast Saccharomyces cerevisiae, a special centromeric DNA sequence assembles a single nucleosome in which two copies of an H3 variant histone (called CENP-A in most organisms) replace the normal H3. (b) How peptide sequences unique to this variant histone (see Figure 4–35) help to assemble additional proteins, some of which form a kinetochore. The yeast kinetochore is unusual in capturing only a single microtubule; humans have much larger centromeres and form kinetochores that can capture 20 or more microtubules (see Figure 4–43). The kinetochore is discussed in detail in Chapter 17. (Adapted from A. Joglekar et al., Nat. Cell Biol. 8:581–585, 2006. with permission from macmillan Publishers ltd.)	Cell_Biology_Alberts. Inactivation of some centromeres and genesis of others de novo seem to have played an essential part in evolution. Different species, even when quite closely Figure 4–42 A model for the structure of a simple centromere. (A) In the yeast Saccharomyces cerevisiae, a special centromeric DNA sequence assembles a single nucleosome in which two copies of an H3 variant histone (called CENP-A in most organisms) replace the normal H3. (b) How peptide sequences unique to this variant histone (see Figure 4–35) help to assemble additional proteins, some of which form a kinetochore. The yeast kinetochore is unusual in capturing only a single microtubule; humans have much larger centromeres and form kinetochores that can capture 20 or more microtubules (see Figure 4–43). The kinetochore is discussed in detail in Chapter 17. (Adapted from A. Joglekar et al., Nat. Cell Biol. 8:581–585, 2006. with permission from macmillan Publishers ltd.)
Cell_Biology_Alberts_918	Cell_Biology_Alberts	Figure 4–43 evidence for the plasticity of human centromere formation. (A) A series of A-T-rich alpha satellite DNA sequences is repeated many thousands of times at each human centromere (red), and is surrounded by pericentric heterochromatin (brown). However, due to an ancient chromosome breakage-and-rejoining event, some human chromosomes contain two blocks of alpha satellite DNA, each of which presumably functioned as a centromere in its original chromosome. Usually, chromosomes with two functional centromeres are not stably propagated because they attach improperly to the spindle and are broken apart during mitosis. In chromosomes that do survive, however, one of the centromeres has somehow become inactivated, even though it contains all the necessary DNA sequences. This allows the chromosome to be stably propagated. (b) In a small fraction (1/2000) of human births, extra chromosomes are observed in cells of the offspring. Some of these extra chromosomes, which have formed from a	Cell_Biology_Alberts. Figure 4–43 evidence for the plasticity of human centromere formation. (A) A series of A-T-rich alpha satellite DNA sequences is repeated many thousands of times at each human centromere (red), and is surrounded by pericentric heterochromatin (brown). However, due to an ancient chromosome breakage-and-rejoining event, some human chromosomes contain two blocks of alpha satellite DNA, each of which presumably functioned as a centromere in its original chromosome. Usually, chromosomes with two functional centromeres are not stably propagated because they attach improperly to the spindle and are broken apart during mitosis. In chromosomes that do survive, however, one of the centromeres has somehow become inactivated, even though it contains all the necessary DNA sequences. This allows the chromosome to be stably propagated. (b) In a small fraction (1/2000) of human births, extra chromosomes are observed in cells of the offspring. Some of these extra chromosomes, which have formed from a
Cell_Biology_Alberts_919	Cell_Biology_Alberts	to be stably propagated. (b) In a small fraction (1/2000) of human births, extra chromosomes are observed in cells of the offspring. Some of these extra chromosomes, which have formed from a breakage event, lack alpha satellite DNA altogether, yet new centromeres (neocentromeres) have arisen from what was originally euchromatic DNA.	Cell_Biology_Alberts. to be stably propagated. (b) In a small fraction (1/2000) of human births, extra chromosomes are observed in cells of the offspring. Some of these extra chromosomes, which have formed from a breakage event, lack alpha satellite DNA altogether, yet new centromeres (neocentromeres) have arisen from what was originally euchromatic DNA.
Cell_Biology_Alberts_920	Cell_Biology_Alberts	The complexity of centromeric chromatin is not illustrated in these diagrams. The alpha satellite DNA that forms centromeric chromatin in humans is packaged into alternating blocks of chromatin. One block is formed from a long string of nucleosomes containing the CENP-A H3 variant histone; the other block contains nucleosomes that are specially marked with dimethyl lysine 4 on the normal H3 histone. Each block is more than a thousand nucleosomes long. This centromeric chromatin is flanked by pericentric heterochromatin, as shown. The pericentric chromatin contains methylated lysine 9 on its H3 histones, along with HP1 protein, and it is an example of “classical” heterochromatin (see Figure 4–39).	Cell_Biology_Alberts. The complexity of centromeric chromatin is not illustrated in these diagrams. The alpha satellite DNA that forms centromeric chromatin in humans is packaged into alternating blocks of chromatin. One block is formed from a long string of nucleosomes containing the CENP-A H3 variant histone; the other block contains nucleosomes that are specially marked with dimethyl lysine 4 on the normal H3 histone. Each block is more than a thousand nucleosomes long. This centromeric chromatin is flanked by pericentric heterochromatin, as shown. The pericentric chromatin contains methylated lysine 9 on its H3 histones, along with HP1 protein, and it is an example of “classical” heterochromatin (see Figure 4–39).
Cell_Biology_Alberts_921	Cell_Biology_Alberts	related, often have different numbers of chromosomes; see Figure 4–14 for an extreme example. As we shall discuss below, detailed genome comparisons show that in many cases the changes in chromosome numbers have arisen through chromosome breakage-and-rejoining events, creating novel chromosomes, some of which must initially have contained abnormal numbers of centromeres—either more than one, or none at all. Yet stable inheritance requires that each chromosome should contain one centromere, and one only. It seems that surplus centromeres must have been inactivated, and/or new centromeres created, so as to allow the rearranged chromosome sets to be stably maintained. The changes in centromere activity just discussed, once established, need to be perpetuated through subsequent cell generations. What could be the mechanism of this type of epigenetic inheritance?	Cell_Biology_Alberts. related, often have different numbers of chromosomes; see Figure 4–14 for an extreme example. As we shall discuss below, detailed genome comparisons show that in many cases the changes in chromosome numbers have arisen through chromosome breakage-and-rejoining events, creating novel chromosomes, some of which must initially have contained abnormal numbers of centromeres—either more than one, or none at all. Yet stable inheritance requires that each chromosome should contain one centromere, and one only. It seems that surplus centromeres must have been inactivated, and/or new centromeres created, so as to allow the rearranged chromosome sets to be stably maintained. The changes in centromere activity just discussed, once established, need to be perpetuated through subsequent cell generations. What could be the mechanism of this type of epigenetic inheritance?
Cell_Biology_Alberts_922	Cell_Biology_Alberts	It has been proposed that de novo centromere formation requires an initial seeding event, involving the formation of a specialized DNA–protein structure that contains nucleosomes formed with the CENP-A variant of histone H3. In humans, this seeding event happens more readily on arrays of alpha satellite DNA than on other DNA sequences. The H3–H4 tetramers from each nucleosome on the parental DNA helix are directly inherited by the sister DNA helices at a replication fork (see Figure 5–32). Therefore, once a set of CENP-A-containing nucleosomes has been assembled on a stretch of DNA, it is easy to understand how a new centromere could be generated in the same place on both daughter chromosomes following each round of cell division. One need only assume that the presence of the CENP-A histone in an inherited nucleosome selectively recruits more CENP-A histone to its newly formed neighbors.	Cell_Biology_Alberts. It has been proposed that de novo centromere formation requires an initial seeding event, involving the formation of a specialized DNA–protein structure that contains nucleosomes formed with the CENP-A variant of histone H3. In humans, this seeding event happens more readily on arrays of alpha satellite DNA than on other DNA sequences. The H3–H4 tetramers from each nucleosome on the parental DNA helix are directly inherited by the sister DNA helices at a replication fork (see Figure 5–32). Therefore, once a set of CENP-A-containing nucleosomes has been assembled on a stretch of DNA, it is easy to understand how a new centromere could be generated in the same place on both daughter chromosomes following each round of cell division. One need only assume that the presence of the CENP-A histone in an inherited nucleosome selectively recruits more CENP-A histone to its newly formed neighbors.
Cell_Biology_Alberts_923	Cell_Biology_Alberts	There are some striking similarities between the formation and maintenance of centromeres and the formation and maintenance of some other regions of heterochromatin. In particular, the entire centromere forms as an all-or-none entity, suggesting that the creation of centromeric chromatin is a highly cooperative process, spreading out from an initial seed in a manner reminiscent of the phenomenon of position effect variegation that we discussed earlier. In both cases, a particular chromatin structure, once formed, seems to be directly inherited on the DNA following each round of chromosome replication. A cooperative recruitment of proteins, along with the action of reader–writer complexes, can thus not only account for the spreading of specific forms of chromatin in space along the chromosome, but also for its propagation across cell generations—from parent cell to daughter cell (Figure 4–44).	Cell_Biology_Alberts. There are some striking similarities between the formation and maintenance of centromeres and the formation and maintenance of some other regions of heterochromatin. In particular, the entire centromere forms as an all-or-none entity, suggesting that the creation of centromeric chromatin is a highly cooperative process, spreading out from an initial seed in a manner reminiscent of the phenomenon of position effect variegation that we discussed earlier. In both cases, a particular chromatin structure, once formed, seems to be directly inherited on the DNA following each round of chromosome replication. A cooperative recruitment of proteins, along with the action of reader–writer complexes, can thus not only account for the spreading of specific forms of chromatin in space along the chromosome, but also for its propagation across cell generations—from parent cell to daughter cell (Figure 4–44).
Cell_Biology_Alberts_924	Cell_Biology_Alberts	Experiments with Frog Embryos Suggest that both Activating and Repressive Chromatin Structures Can be Inherited Epigenetically Epigenetic inheritance plays a central part in the creation of multicellular organisms. Their differentiated cell types become established during development, and persist thereafter even through repeated cell-division cycles. The daughters of a liver cell persist as liver cells, those of an epidermal cell as epidermal cells, and so on, even though they all contain the same genome; and this is because distinctive patterns of gene expression are passed on faithfully from parent cell to daughter cell. Chromatin structure has a role in this epigenetic transmission of information from one cell generation to the next.	Cell_Biology_Alberts. Experiments with Frog Embryos Suggest that both Activating and Repressive Chromatin Structures Can be Inherited Epigenetically Epigenetic inheritance plays a central part in the creation of multicellular organisms. Their differentiated cell types become established during development, and persist thereafter even through repeated cell-division cycles. The daughters of a liver cell persist as liver cells, those of an epidermal cell as epidermal cells, and so on, even though they all contain the same genome; and this is because distinctive patterns of gene expression are passed on faithfully from parent cell to daughter cell. Chromatin structure has a role in this epigenetic transmission of information from one cell generation to the next.
Cell_Biology_Alberts_925	Cell_Biology_Alberts	One type of evidence comes from studies in which the nucleus of a cell from a frog or tadpole is transplanted into a frog egg whose own nucleus has been removed (an enucleated egg). In a classic set of experiments performed in 1968, it was shown that a nucleus taken from a differentiated donor cell can be reprogrammed in this way to support development of a whole new tadpole (see Figure 7–2). But this reprogramming occurs only with difficulty, and it becomes less and less efficient as nuclei from older animals are used. Thus, for example, less than 2% of the enucleated eggs injected with a nucleus from a tadpole epithelial cell developed to the swimming tadpole stage, compared with 35% when the donor nuclei were taken instead from an early (gastrula-stage) embryo. With new experimental tools, the cause of this resistance to reprogramming can now be traced. It arises, at least in part, because specific chromatin structures in the original differentiated nucleus tend to persist and be	Cell_Biology_Alberts. One type of evidence comes from studies in which the nucleus of a cell from a frog or tadpole is transplanted into a frog egg whose own nucleus has been removed (an enucleated egg). In a classic set of experiments performed in 1968, it was shown that a nucleus taken from a differentiated donor cell can be reprogrammed in this way to support development of a whole new tadpole (see Figure 7–2). But this reprogramming occurs only with difficulty, and it becomes less and less efficient as nuclei from older animals are used. Thus, for example, less than 2% of the enucleated eggs injected with a nucleus from a tadpole epithelial cell developed to the swimming tadpole stage, compared with 35% when the donor nuclei were taken instead from an early (gastrula-stage) embryo. With new experimental tools, the cause of this resistance to reprogramming can now be traced. It arises, at least in part, because specific chromatin structures in the original differentiated nucleus tend to persist and be
Cell_Biology_Alberts_926	Cell_Biology_Alberts	the cause of this resistance to reprogramming can now be traced. It arises, at least in part, because specific chromatin structures in the original differentiated nucleus tend to persist and be transmitted through the many cell-division cycles required for embryonic development. In experiments with Xenopus embryos, specific forms of either repressive or active chromatin structures could be demonstrated to persist through as many as 24 cell divisions, causing the misplaced expression of genes. Figure 4–45 briefly describes one such experiment,	Cell_Biology_Alberts. the cause of this resistance to reprogramming can now be traced. It arises, at least in part, because specific chromatin structures in the original differentiated nucleus tend to persist and be transmitted through the many cell-division cycles required for embryonic development. In experiments with Xenopus embryos, specific forms of either repressive or active chromatin structures could be demonstrated to persist through as many as 24 cell divisions, causing the misplaced expression of genes. Figure 4–45 briefly describes one such experiment,
Cell_Biology_Alberts_927	Cell_Biology_Alberts	Figure 4–44 How the packaging of DNA in chromatin can be inherited following chromosome replication. In this model, some of the specialized chromatin components are distributed to each sister chromosome after DNA duplication, along with the specially marked nucleosomes that they bind. After DNA replication, the inherited nucleosomes that are specially modified, acting in concert with the inherited chromatin components, change the pattern of histone modification on the newly formed nucleosomes nearby. This creates new binding sites for the same chromatin components, which then assemble to complete the structure. The latter process is likely to involve reader– writer–remodeling complexes operating in a manner similar to that previously illustrated in Figure 4–40.	Cell_Biology_Alberts. Figure 4–44 How the packaging of DNA in chromatin can be inherited following chromosome replication. In this model, some of the specialized chromatin components are distributed to each sister chromosome after DNA duplication, along with the specially marked nucleosomes that they bind. After DNA replication, the inherited nucleosomes that are specially modified, acting in concert with the inherited chromatin components, change the pattern of histone modification on the newly formed nucleosomes nearby. This creates new binding sites for the same chromatin components, which then assemble to complete the structure. The latter process is likely to involve reader– writer–remodeling complexes operating in a manner similar to that previously illustrated in Figure 4–40.
Cell_Biology_Alberts_928	Cell_Biology_Alberts	inject normal no injection inject mutant H3.3 mRNA (control) H3.3 mRNA cells analyzed for MyoD expression and for H3.3 histone on MyoD promoter focused on chromatin containing the histone variant, H3.3. We shall return to these phenomena in the final section of Chapter 22, where we discuss stem cells and the ways in which one cell type can be converted into another. Although a great deal remains to be learned about the functions of different chromatin structures, the packaging of DNA into nucleosomes was probably crucial for the evolution of eukaryotes like ourselves. To form a complex multicellular organism, the cells in different lineages must specialize by changing the accessibility and activity of many hundreds of genes. As described in Chapter 21, this process depends on cell memory: each cell holds a record of its past developmental history in the regulatory circuits that control its many genes. That record, it seems, is partly stored in the structure of the chromatin.	Cell_Biology_Alberts. inject normal no injection inject mutant H3.3 mRNA (control) H3.3 mRNA cells analyzed for MyoD expression and for H3.3 histone on MyoD promoter focused on chromatin containing the histone variant, H3.3. We shall return to these phenomena in the final section of Chapter 22, where we discuss stem cells and the ways in which one cell type can be converted into another. Although a great deal remains to be learned about the functions of different chromatin structures, the packaging of DNA into nucleosomes was probably crucial for the evolution of eukaryotes like ourselves. To form a complex multicellular organism, the cells in different lineages must specialize by changing the accessibility and activity of many hundreds of genes. As described in Chapter 21, this process depends on cell memory: each cell holds a record of its past developmental history in the regulatory circuits that control its many genes. That record, it seems, is partly stored in the structure of the chromatin.
Cell_Biology_Alberts_929	Cell_Biology_Alberts	Although bacteria also have cell memory mechanisms, the complexity of the memory circuits in higher eukaryotes is unparalleled. Strategies based on local variations in chromatin structure, unique to eukaryotes, can enable individual genes, once they are switched on or switched off, to stay in that state until some new factor acts to reverse it. At one extreme are structures like centromeric chromatin that, once established, are stably inherited from one cell generation to the next. Likewise, the major “classical” type of heterochromatin, which contains long arrays of the HP1 protein (see Figure 4–39), can persist stably throughout life. In contrast, a form of condensed chromatin that is created by the Polycomb group of proteins serves to silence genes that must be kept inactive in some conditions, but are active in others. The latter mechanism governs the expression of a large number of genes that encode transcription regulators important in early embryonic development, as discussed	Cell_Biology_Alberts. Although bacteria also have cell memory mechanisms, the complexity of the memory circuits in higher eukaryotes is unparalleled. Strategies based on local variations in chromatin structure, unique to eukaryotes, can enable individual genes, once they are switched on or switched off, to stay in that state until some new factor acts to reverse it. At one extreme are structures like centromeric chromatin that, once established, are stably inherited from one cell generation to the next. Likewise, the major “classical” type of heterochromatin, which contains long arrays of the HP1 protein (see Figure 4–39), can persist stably throughout life. In contrast, a form of condensed chromatin that is created by the Polycomb group of proteins serves to silence genes that must be kept inactive in some conditions, but are active in others. The latter mechanism governs the expression of a large number of genes that encode transcription regulators important in early embryonic development, as discussed
Cell_Biology_Alberts_930	Cell_Biology_Alberts	but are active in others. The latter mechanism governs the expression of a large number of genes that encode transcription regulators important in early embryonic development, as discussed in Chapter 21. There are many other variant forms of chromatin, some with much shorter lifetimes, often less than the division time of the cell. We shall say more about the variety of chromatin types in the next section.	Cell_Biology_Alberts. but are active in others. The latter mechanism governs the expression of a large number of genes that encode transcription regulators important in early embryonic development, as discussed in Chapter 21. There are many other variant forms of chromatin, some with much shorter lifetimes, often less than the division time of the cell. We shall say more about the variety of chromatin types in the next section.
Cell_Biology_Alberts_931	Cell_Biology_Alberts	Figure 4–45 evidence for the inheritance of a gene-activating chromatin state.	Cell_Biology_Alberts. Figure 4–45 evidence for the inheritance of a gene-activating chromatin state.
Cell_Biology_Alberts_932	Cell_Biology_Alberts	The well-characterized MyoD gene encodes a master transcription regulatory protein for muscle, myoD (see p. 399). This gene is normally turned on in the indicated region of the young embryo where somites form. when a nucleus from this region is injected into an enucleated egg as shown, many of the progeny cell nuclei abnormally express the myoD protein in non-muscle regions of the “nuclear transplant embryo” that forms. This abnormal expression can be attributed to maintenance of the MyoD promoter region in its active chromatin state through the many cycles of cell division that produce the blastula-stage embryo—a so-called “epigenetic memory” that persists in this case in the absence of transcription. The active chromatin surrounding the MyoD promoter contains the variant histone H3.3 (see Figure 4–35) in a lys4 methylated form. As indicated, an overproduction of this histone caused by injecting excess mRNA encoding the normal H3.3 protein increases both H3.3 occupancy on the MyoD	Cell_Biology_Alberts. The well-characterized MyoD gene encodes a master transcription regulatory protein for muscle, myoD (see p. 399). This gene is normally turned on in the indicated region of the young embryo where somites form. when a nucleus from this region is injected into an enucleated egg as shown, many of the progeny cell nuclei abnormally express the myoD protein in non-muscle regions of the “nuclear transplant embryo” that forms. This abnormal expression can be attributed to maintenance of the MyoD promoter region in its active chromatin state through the many cycles of cell division that produce the blastula-stage embryo—a so-called “epigenetic memory” that persists in this case in the absence of transcription. The active chromatin surrounding the MyoD promoter contains the variant histone H3.3 (see Figure 4–35) in a lys4 methylated form. As indicated, an overproduction of this histone caused by injecting excess mRNA encoding the normal H3.3 protein increases both H3.3 occupancy on the MyoD
Cell_Biology_Alberts_933	Cell_Biology_Alberts	(see Figure 4–35) in a lys4 methylated form. As indicated, an overproduction of this histone caused by injecting excess mRNA encoding the normal H3.3 protein increases both H3.3 occupancy on the MyoD promoter and the epigenetic myoD production, whereas injection of an mRNA producing a mutant form of H3.3 that cannot be methylated at lys4 reduces the epigenetic myoD production. Such experiments provide evidence that an inherited chromatin state underlies the epigenetic memory observed. (Adapted from R.k. Ng and J.b. gurdon, Nat. Cell Biol. 10:102–109, 2008. with permission from macmillan Publishers ltd.)	Cell_Biology_Alberts. (see Figure 4–35) in a lys4 methylated form. As indicated, an overproduction of this histone caused by injecting excess mRNA encoding the normal H3.3 protein increases both H3.3 occupancy on the MyoD promoter and the epigenetic myoD production, whereas injection of an mRNA producing a mutant form of H3.3 that cannot be methylated at lys4 reduces the epigenetic myoD production. Such experiments provide evidence that an inherited chromatin state underlies the epigenetic memory observed. (Adapted from R.k. Ng and J.b. gurdon, Nat. Cell Biol. 10:102–109, 2008. with permission from macmillan Publishers ltd.)
Cell_Biology_Alberts_934	Cell_Biology_Alberts	In the chromosomes of eukaryotes, DNA is uniformly assembled into nucleosomes, but a variety of different chromatin structures is possible. This variety is based on a large set of reversible covalent modifications of the four histones in the nucleosome core. These modifications include the mono-, di-, and trimethylation of many different lysine side chains, an important reaction that is incompatible with the acetylation that can occur on the same lysines. Specific combinations of the modifications mark many nucleosomes, governing their interactions with other proteins. These marks are read when protein modules that are part of a larger protein complex bind to the modified nucleosomes in a region of chromatin. These reader proteins then attract additional proteins that perform various functions.	Cell_Biology_Alberts. In the chromosomes of eukaryotes, DNA is uniformly assembled into nucleosomes, but a variety of different chromatin structures is possible. This variety is based on a large set of reversible covalent modifications of the four histones in the nucleosome core. These modifications include the mono-, di-, and trimethylation of many different lysine side chains, an important reaction that is incompatible with the acetylation that can occur on the same lysines. Specific combinations of the modifications mark many nucleosomes, governing their interactions with other proteins. These marks are read when protein modules that are part of a larger protein complex bind to the modified nucleosomes in a region of chromatin. These reader proteins then attract additional proteins that perform various functions.
Cell_Biology_Alberts_935	Cell_Biology_Alberts	Some reader protein complexes contain a histone-modifying enzyme, such as a histone lysine methylase, that “writes” the same mark that the reader recognizes. A reader–writer–remodeling complex of this type can spread a specific form of chromatin along a chromosome. In particular, large regions of condensed heterochromatin are thought to be formed in this way. Heterochromatin is commonly found around centromeres and near telomeres, but it is also present at many other positions in chromosomes. The tight packaging of DNA into heterochromatin usually silences the genes within it.	Cell_Biology_Alberts. Some reader protein complexes contain a histone-modifying enzyme, such as a histone lysine methylase, that “writes” the same mark that the reader recognizes. A reader–writer–remodeling complex of this type can spread a specific form of chromatin along a chromosome. In particular, large regions of condensed heterochromatin are thought to be formed in this way. Heterochromatin is commonly found around centromeres and near telomeres, but it is also present at many other positions in chromosomes. The tight packaging of DNA into heterochromatin usually silences the genes within it.
Cell_Biology_Alberts_936	Cell_Biology_Alberts	The phenomenon of position effect variegation provides strong evidence for the inheritance of condensed states of chromatin from one cell generation to the next. A similar mechanism appears to be responsible for maintaining the specialized chromatin at centromeres. More generally, the ability to propagate specific chromatin structures across cell generations makes possible an epigenetic cell memory process that plays a role in maintaining the set of different cell states required by complex multicellular organisms.	Cell_Biology_Alberts. The phenomenon of position effect variegation provides strong evidence for the inheritance of condensed states of chromatin from one cell generation to the next. A similar mechanism appears to be responsible for maintaining the specialized chromatin at centromeres. More generally, the ability to propagate specific chromatin structures across cell generations makes possible an epigenetic cell memory process that plays a role in maintaining the set of different cell states required by complex multicellular organisms.
Cell_Biology_Alberts_937	Cell_Biology_Alberts	Having discussed the DNA and protein molecules from which the chromatin fiber is made, we now turn to the organization of the chromosome on a more global scale and the way in which its various domains are arranged in space. As a 30-nm fiber, a typical human chromosome would still be 0.1 cm in length and able to span the nucleus more than 100 times. Clearly, there must be a still higher level of folding, even in interphase chromosomes. Although the molecular details are still largely a mystery, this higher-order packaging almost certainly involves the folding of the chromatin into a series of loops and coils. This chromatin packing is fluid, frequently changing in response to the needs of the cell.	Cell_Biology_Alberts. Having discussed the DNA and protein molecules from which the chromatin fiber is made, we now turn to the organization of the chromosome on a more global scale and the way in which its various domains are arranged in space. As a 30-nm fiber, a typical human chromosome would still be 0.1 cm in length and able to span the nucleus more than 100 times. Clearly, there must be a still higher level of folding, even in interphase chromosomes. Although the molecular details are still largely a mystery, this higher-order packaging almost certainly involves the folding of the chromatin into a series of loops and coils. This chromatin packing is fluid, frequently changing in response to the needs of the cell.
Cell_Biology_Alberts_938	Cell_Biology_Alberts	We begin this section by describing some unusual interphase chromosomes that can be easily visualized. Exceptional though they are, these special cases reveal features that are thought to be representative of all interphase chromosomes. Moreover, they provide ways to investigate some fundamental aspects of chromatin structure that we have touched on in the previous section. Next, we describe how a typical interphase chromosome is arranged in the mammalian cell nucleus. Finally, we shall discuss the additional tenfold compaction that chromosomes undergo in the passage from interphase to mitosis. Chromosomes Are Folded into large loops of Chromatin	Cell_Biology_Alberts. We begin this section by describing some unusual interphase chromosomes that can be easily visualized. Exceptional though they are, these special cases reveal features that are thought to be representative of all interphase chromosomes. Moreover, they provide ways to investigate some fundamental aspects of chromatin structure that we have touched on in the previous section. Next, we describe how a typical interphase chromosome is arranged in the mammalian cell nucleus. Finally, we shall discuss the additional tenfold compaction that chromosomes undergo in the passage from interphase to mitosis. Chromosomes Are Folded into large loops of Chromatin
Cell_Biology_Alberts_939	Cell_Biology_Alberts	Chromosomes Are Folded into large loops of Chromatin Insight into the structure of the chromosomes in interphase cells has come from studies of the stiff and enormously extended chromosomes in growing amphibian oocytes (immature eggs). These very unusual lampbrush chromosomes (the largest chromosomes known), paired in preparation for meiosis, are clearly visible even in the light microscope, where they are seen to be organized into a series of large chromatin loops emanating from a linear chromosomal axis (Figure 4–46 and Figure 4–47). In these chromosomes, a given loop always contains the same DNA sequence that remains extended in the same manner as the oocyte grows. These chromosomes are producing large amounts of RNA for the oocyte, and most of the genes Figure 4–46 A model for the chromatin domains in a lampbrush chromosome.	Cell_Biology_Alberts. Chromosomes Are Folded into large loops of Chromatin Insight into the structure of the chromosomes in interphase cells has come from studies of the stiff and enormously extended chromosomes in growing amphibian oocytes (immature eggs). These very unusual lampbrush chromosomes (the largest chromosomes known), paired in preparation for meiosis, are clearly visible even in the light microscope, where they are seen to be organized into a series of large chromatin loops emanating from a linear chromosomal axis (Figure 4–46 and Figure 4–47). In these chromosomes, a given loop always contains the same DNA sequence that remains extended in the same manner as the oocyte grows. These chromosomes are producing large amounts of RNA for the oocyte, and most of the genes Figure 4–46 A model for the chromatin domains in a lampbrush chromosome.
Cell_Biology_Alberts_940	Cell_Biology_Alberts	Figure 4–46 A model for the chromatin domains in a lampbrush chromosome. Shown is a small portion of one pair of sister chromatids. Here, two identical DNA double helices are aligned side by side, packaged into different types of chromatin. The set of lampbrush chromosomes in many amphibians contains a total of about 10,000 loops resembling those shown here. The rest of the DNA in each chromosome (the great majority) remains highly condensed. Four copies of each loop are present in the cell, since each lampbrush chromosome consists of two aligned sets of paired chromatids. This four-stranded structure is characteristic of this stage of development of the oocyte, which has arrested at the diplotene stage of meiosis; see Figure 17–56. present in the DNA loops are being actively expressed. The majority of the DNA, however, is not in loops but remains highly condensed on the chromosome axis, where genes are generally not expressed.	Cell_Biology_Alberts. Figure 4–46 A model for the chromatin domains in a lampbrush chromosome. Shown is a small portion of one pair of sister chromatids. Here, two identical DNA double helices are aligned side by side, packaged into different types of chromatin. The set of lampbrush chromosomes in many amphibians contains a total of about 10,000 loops resembling those shown here. The rest of the DNA in each chromosome (the great majority) remains highly condensed. Four copies of each loop are present in the cell, since each lampbrush chromosome consists of two aligned sets of paired chromatids. This four-stranded structure is characteristic of this stage of development of the oocyte, which has arrested at the diplotene stage of meiosis; see Figure 17–56. present in the DNA loops are being actively expressed. The majority of the DNA, however, is not in loops but remains highly condensed on the chromosome axis, where genes are generally not expressed.
Cell_Biology_Alberts_941	Cell_Biology_Alberts	It is thought that the interphase chromosomes of all eukaryotes are similarly arranged in loops. Although these loops are normally too small and fragile to be easily observed in a light microscope, other methods can be used to infer their presence. For example, modern DNA technologies have made it possible to assess the frequency with which any two loci along an interphase chromosome are held together, thus revealing likely candidates for the sites on chromatin that form the bases of loop structures (Figure 4–48). These experiments and others suggest that the DNA in human chromosomes is likely to be organized into loops of various lengths. A typical loop might contain between 50,000 and 200,000 nucleotide pairs of DNA, although loops of a million nucleotide pairs have also been suggested (Figure 4–49).	Cell_Biology_Alberts. It is thought that the interphase chromosomes of all eukaryotes are similarly arranged in loops. Although these loops are normally too small and fragile to be easily observed in a light microscope, other methods can be used to infer their presence. For example, modern DNA technologies have made it possible to assess the frequency with which any two loci along an interphase chromosome are held together, thus revealing likely candidates for the sites on chromatin that form the bases of loop structures (Figure 4–48). These experiments and others suggest that the DNA in human chromosomes is likely to be organized into loops of various lengths. A typical loop might contain between 50,000 and 200,000 nucleotide pairs of DNA, although loops of a million nucleotide pairs have also been suggested (Figure 4–49).
Cell_Biology_Alberts_942	Cell_Biology_Alberts	Further insight has come from another unusual class of cells—the polytene cells of flies, such as the fruit fly Drosophila. Some types of cells, in many organisms, grow abnormally large through multiple cycles of DNA synthesis without cell division. Such cells, containing increased numbers of standard chromosomes, are said to be polyploid. In the salivary glands of fly larvae, this process is taken to an extreme degree, creating huge cells that contain hundreds or thousands of copies of the Figure 4–47 lampbrush chromosomes.	Cell_Biology_Alberts. Further insight has come from another unusual class of cells—the polytene cells of flies, such as the fruit fly Drosophila. Some types of cells, in many organisms, grow abnormally large through multiple cycles of DNA synthesis without cell division. Such cells, containing increased numbers of standard chromosomes, are said to be polyploid. In the salivary glands of fly larvae, this process is taken to an extreme degree, creating huge cells that contain hundreds or thousands of copies of the Figure 4–47 lampbrush chromosomes.
Cell_Biology_Alberts_943	Cell_Biology_Alberts	(A) A light micrograph of lampbrush chromosomes in an amphibian oocyte. Early in oocyte differentiation, each chromosome replicates to begin meiosis, and the homologous replicated chromosomes pair to form this highly extended structure containing a total of four replicated DNA double helices, or chromatids. The lampbrush chromosome stage persists for months or years, while the oocyte builds up a supply of materials required for its ultimate development into a new individual. (b) An enlarged region of a similar chromosome, stained with a fluorescent reagent that makes the loops active in RNA synthesis clearly visible. (Courtesy of Joseph g. gall.) genome. Moreover, in this case, all the copies of each chromosome are aligned side by side in exact register, like drinking straws in a box, to create giant polytene chromosomes. These allow features to be detected that are thought to be shared with ordinary interphase chromosomes, but are normally hard to see.	Cell_Biology_Alberts. (A) A light micrograph of lampbrush chromosomes in an amphibian oocyte. Early in oocyte differentiation, each chromosome replicates to begin meiosis, and the homologous replicated chromosomes pair to form this highly extended structure containing a total of four replicated DNA double helices, or chromatids. The lampbrush chromosome stage persists for months or years, while the oocyte builds up a supply of materials required for its ultimate development into a new individual. (b) An enlarged region of a similar chromosome, stained with a fluorescent reagent that makes the loops active in RNA synthesis clearly visible. (Courtesy of Joseph g. gall.) genome. Moreover, in this case, all the copies of each chromosome are aligned side by side in exact register, like drinking straws in a box, to create giant polytene chromosomes. These allow features to be detected that are thought to be shared with ordinary interphase chromosomes, but are normally hard to see.
Cell_Biology_Alberts_944	Cell_Biology_Alberts	When polytene chromosomes from a fly’s salivary glands are viewed in the light microscope, distinct alternating dark bands and light interbands are visible (Figure 4–50), each formed from a thousand identical DNA sequences arranged side by side in register. About 95% of the DNA in polytene chromosomes is in bands, and 5% is in interbands. A very thin band can contain 3000 nucleotide pairs, while a thick band may contain 200,000 nucleotide pairs in each of its chromatin strands. The chromatin in each band appears dark because the DNA is more condensed than the DNA in interbands; it may also contain a higher concentration of proteins (Figure 4–51). This banding pattern seems to reflect the same sort of organization detected in the amphibian lampbrush chromosomes described earlier.	Cell_Biology_Alberts. When polytene chromosomes from a fly’s salivary glands are viewed in the light microscope, distinct alternating dark bands and light interbands are visible (Figure 4–50), each formed from a thousand identical DNA sequences arranged side by side in register. About 95% of the DNA in polytene chromosomes is in bands, and 5% is in interbands. A very thin band can contain 3000 nucleotide pairs, while a thick band may contain 200,000 nucleotide pairs in each of its chromatin strands. The chromatin in each band appears dark because the DNA is more condensed than the DNA in interbands; it may also contain a higher concentration of proteins (Figure 4–51). This banding pattern seems to reflect the same sort of organization detected in the amphibian lampbrush chromosomes described earlier.
Cell_Biology_Alberts_945	Cell_Biology_Alberts	There are approximately 3700 bands and 3700 interbands in the complete set of Drosophila polytene chromosomes. The bands can be recognized by their different thicknesses and spacings, and each one has been given a number to generate a chromosome “map” that has been indexed to the finished genome sequence of this fly. The Drosophila polytene chromosomes provide a good starting point for examining how chromatin is organized on a large scale. In the previous section, we saw that there are many forms of chromatin, each of which contains nucleosomes with a different combination of modified histones. Specific sets of non-histone proteins assemble on these nucleosomes to affect biological function in different ways. Recruitment of some of these non-histone proteins can spread for long distances along the DNA, imparting a similar chromatin structure to broad tracts DNA product is obtained only if proteins hold the two DNA sequences close together in the cell	Cell_Biology_Alberts. There are approximately 3700 bands and 3700 interbands in the complete set of Drosophila polytene chromosomes. The bands can be recognized by their different thicknesses and spacings, and each one has been given a number to generate a chromosome “map” that has been indexed to the finished genome sequence of this fly. The Drosophila polytene chromosomes provide a good starting point for examining how chromatin is organized on a large scale. In the previous section, we saw that there are many forms of chromatin, each of which contains nucleosomes with a different combination of modified histones. Specific sets of non-histone proteins assemble on these nucleosomes to affect biological function in different ways. Recruitment of some of these non-histone proteins can spread for long distances along the DNA, imparting a similar chromatin structure to broad tracts DNA product is obtained only if proteins hold the two DNA sequences close together in the cell
Cell_Biology_Alberts_946	Cell_Biology_Alberts	Figure 4–48 A method for determining the position of loops in interphase chromosomes. In this technique, known as the chromosome conformation capture (3C) method, cells are treated with formaldehyde to create the indicated covalent DNA–protein and DNA–DNA cross-links. The DNA is then treated with an enzyme (a restriction nuclease) that chops the DNA into many pieces, cutting at strictly defined nucleotide sequences and forming sets of identical “cohesive ends” (see Figure 8–28). The cohesive ends can be made to join through their complementary base-pairing. Importantly, prior to the ligation step shown, the DNA is diluted so that the fragments that have been kept in close proximity to each other (through cross-linking) are the ones most likely to join. Finally, the cross-links are reversed and the newly ligated fragments of DNA are identified and quantified by PCR (the polymerase chain reaction, described in Chapter 8). From the results, combined with DNA sequence information, one can	Cell_Biology_Alberts. Figure 4–48 A method for determining the position of loops in interphase chromosomes. In this technique, known as the chromosome conformation capture (3C) method, cells are treated with formaldehyde to create the indicated covalent DNA–protein and DNA–DNA cross-links. The DNA is then treated with an enzyme (a restriction nuclease) that chops the DNA into many pieces, cutting at strictly defined nucleotide sequences and forming sets of identical “cohesive ends” (see Figure 8–28). The cohesive ends can be made to join through their complementary base-pairing. Importantly, prior to the ligation step shown, the DNA is diluted so that the fragments that have been kept in close proximity to each other (through cross-linking) are the ones most likely to join. Finally, the cross-links are reversed and the newly ligated fragments of DNA are identified and quantified by PCR (the polymerase chain reaction, described in Chapter 8). From the results, combined with DNA sequence information, one can
Cell_Biology_Alberts_947	Cell_Biology_Alberts	and the newly ligated fragments of DNA are identified and quantified by PCR (the polymerase chain reaction, described in Chapter 8). From the results, combined with DNA sequence information, one can derive models for the interphase conformation of chromosomes.	Cell_Biology_Alberts. and the newly ligated fragments of DNA are identified and quantified by PCR (the polymerase chain reaction, described in Chapter 8). From the results, combined with DNA sequence information, one can derive models for the interphase conformation of chromosomes.
Cell_Biology_Alberts_948	Cell_Biology_Alberts	Figure 4–49 A model for the organization of an interphase chromosome. A section of an interphase chromosome is shown folded into a series of looped domains, each containing perhaps 50,000–200,000 or more nucleotide pairs of double-helical DNA condensed into a chromatin fiber. The chromatin in each individual loop is further condensed through poorly understood folding processes that are reversed when the cell requires direct access to the DNA packaged in the loop. Neither the composition of the postulated chromosomal axis nor how the folded chromatin fiber is anchored to it is clear. However, in mitotic chromosomes, the bases of the chromosomal loops are enriched both in condensins (discussed below) and in DNA topoisomerase II enzymes (discussed in Chapter 5), two proteins that may form much of the axis at metaphase.	Cell_Biology_Alberts. Figure 4–49 A model for the organization of an interphase chromosome. A section of an interphase chromosome is shown folded into a series of looped domains, each containing perhaps 50,000–200,000 or more nucleotide pairs of double-helical DNA condensed into a chromatin fiber. The chromatin in each individual loop is further condensed through poorly understood folding processes that are reversed when the cell requires direct access to the DNA packaged in the loop. Neither the composition of the postulated chromosomal axis nor how the folded chromatin fiber is anchored to it is clear. However, in mitotic chromosomes, the bases of the chromosomal loops are enriched both in condensins (discussed below) and in DNA topoisomerase II enzymes (discussed in Chapter 5), two proteins that may form much of the axis at metaphase.
Cell_Biology_Alberts_949	Cell_Biology_Alberts	normal mitotic right arm of chromosomes at chromosome 2 same scale region where two homologous chromosomes are separated left arm of chromosome 2 left arm of chromocenter chromosome 3 20 µm right arm of chromosome 3 of the genome (see Figure 4–40). Such regions, where all of the chromatin has a similar structure, are separated from neighboring domains by barrier proteins (see Figure 4–41). At low resolution, the interphase chromosome can therefore be considered as a mosaic of chromatin structures, each containing particular nucleosome modifications associated with a particular set of non-histone proteins. Polytene chromosomes allow us to see details of this mosaic of domains in the light microscope, as well as to observe some of the changes associated with gene expression. There Are multiple Forms of Chromatin	Cell_Biology_Alberts. normal mitotic right arm of chromosomes at chromosome 2 same scale region where two homologous chromosomes are separated left arm of chromosome 2 left arm of chromocenter chromosome 3 20 µm right arm of chromosome 3 of the genome (see Figure 4–40). Such regions, where all of the chromatin has a similar structure, are separated from neighboring domains by barrier proteins (see Figure 4–41). At low resolution, the interphase chromosome can therefore be considered as a mosaic of chromatin structures, each containing particular nucleosome modifications associated with a particular set of non-histone proteins. Polytene chromosomes allow us to see details of this mosaic of domains in the light microscope, as well as to observe some of the changes associated with gene expression. There Are multiple Forms of Chromatin