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  • Review Article
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Determinants and dynamics of genome accessibility

Key Points

  • Chromatin packaging of genomic DNA restricts accessibility for regulatory proteins but also provides an opportunity to regulate genomic function by modulating nucleosome position and local chromatin structure.

  • Genome-wide profiles of nucleosome localization reveal defined chromatin architecture at functional regulatory sites, such as promoters and enhancers.

  • Nucleosome localization at cis regulatory regions is influenced by several determinants, including DNA sequence, competitive transcription-factor binding and ATP-dependent nucleosome remodelling.

  • Post-translational histone modifications and deposition of histone variants coincide with nucleosomal patterns at regulatory sites where they might specify and facilitate dynamic regulation of DNA accessibility.

  • The initiation of replication occurs at origins of replication (ORIs). Positions of ORIs and their activity appear to depend on nucleosomal organization and modification.

  • The DNA repair machinery has evolved strategies to sense and repair damage in the context of chromatin.

Abstract

In eukaryotes, all DNA-templated reactions occur in the context of chromatin. Nucleosome packaging inherently restricts DNA accessibility for regulatory proteins but also provides an opportunity to regulate DNA-based processes through modulating nucleosome positions and local chromatin structure. Recent advances in genome-scale methods are yielding increasingly detailed profiles of the genomic distribution of nucleosomes, their modifications and their modifiers. The picture now emerging is one in which the dynamic control of genome accessibility is governed by contributions from DNA sequence, ATP-dependent chromatin remodelling and nucleosome modifications. Here we discuss the interplay of these processes by reviewing our current understanding of how chromatin access contributes to the regulation of transcription, replication and repair.

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Figure 1: Chromatin structure and DNA accessibility at genes.
Figure 2: Mobility and stability of nucleosomes.
Figure 3: Local chromatin structure relates to DNA replication timing.
Figure 4: Creating access for DNA repair.

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References

  1. Felsenfeld, G. & Groudine, M. Controlling the double helix. Nature 421, 448–453 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Kaplan, N. et al. The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458, 362–366 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Zhang, Y. et al. Intrinsic histone-DNA interactions are not the major determinant of nucleosome positions in vivo. Nature Struct. Mol. Biol. 16, 847–852 (2009).

    Article  CAS  Google Scholar 

  4. Segal, E. & Widom, J. What controls nucleosome positions? Trends Genet. 25, 335–343 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Workman, J. L. & Kingston, R. E. Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu. Rev. Biochem. 67, 545–579 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Talbert, P. B. & Henikoff, S. Histone variants — ancient wrap artists of the epigenome. Nature Rev. Mol. Cell Biol. 11, 264–275 (2010).

    Article  CAS  Google Scholar 

  9. Albert, I. et al. Translational and rotational settings of H2A.Z nucleosomes across the Saccharomyces cerevisiae genome. Nature 446, 572–576 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Segal, E. et al. A genomic code for nucleosome positioning. Nature 442, 772–778 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yuan, G. C. et al. Genome-scale identification of nucleosome positions in S. cerevisiae. Science 309, 626–630 (2005). This was the first high-resolution genome-wide study of nucleosome distribution. It indicated that conserved DNA sequences contribute to the stereotypic nucleosome arrangement found at most yeast promoters.

    Article  CAS  PubMed  Google Scholar 

  13. Boyle, A. P. et al. High-resolution mapping and characterization of open chromatin across the genome. Cell 132, 311–322 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wu, C., Bingham, P. M., Livak, K. J., Holmgren, R. & Elgin, S. C. The chromatin structure of specific genes: I. Evidence for higher order domains of defined DNA sequence. Cell 16, 797–806 (1979). This was the first demonstration that DNase I sensitivity and chromatin structure at gene promoters dynamically respond to transcriptional regulation.

    Article  CAS  PubMed  Google Scholar 

  15. Wu, C. The 5′ ends of Drosophila heat shock genes in chromatin are hypersensitive to DNase I. Nature 286, 854–860 (1980).

    Article  CAS  PubMed  Google Scholar 

  16. Mito, Y., Henikoff, J. G. & Henikoff, S. Histone replacement marks the boundaries of cis-regulatory domains. Science 315, 1408–1411 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Nagy, P. L., Cleary, M. L., Brown, P. O. & Lieb, J. D. Genomewide demarcation of RNA polymerase II transcription units revealed by physical fractionation of chromatin. Proc. Natl Acad. Sci. USA 100, 6364–6369 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sabo, P. J. et al. Genome-wide identification of DNaseI hypersensitive sites using active chromatin sequence libraries. Proc. Natl Acad. Sci. USA 101, 4537–4542 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Crawford, G. E. et al. Identifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites. Proc. Natl Acad. Sci. USA 101, 992–997 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Weintraub, H. & Groudine, M. Chromosomal subunits in active genes have an altered conformation. Science 193, 848–856 (1976). This paper was the first to describe differential sensitivity of active and repressed genes to DNase I digestion.

    Article  CAS  PubMed  Google Scholar 

  21. Bulger, M. et al. A complex chromatin landscape revealed by patterns of nuclease sensitivity and histone modification within the mouse β-globin locus. Mol. Cell. Biol. 23, 5234–5244 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Noll, M., Thomas, J. O. & Kornberg, R. D. Preparation of native chromatin and damage caused by shearing. Science 187, 1203–1206 (1975).

    Article  CAS  PubMed  Google Scholar 

  23. Schones, D. E. et al. Dynamic regulation of nucleosome positioning in the human genome. Cell 132, 887–898 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Mavrich, T. N. et al. Nucleosome organization in the Drosophila genome. Nature 453, 358–362 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Valouev, A. et al. Determinants of nucleosome organization in primary human cells. Nature 474, 516–520 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jessen, W. J., Hoose, S. A., Kilgore, J. A. & Kladde, M. P. Active PHO5 chromatin encompasses variable numbers of nucleosomes at individual promoters. Nature Struct. Mol. Biol. 13, 256–263 (2006).

    Article  CAS  Google Scholar 

  27. Fatemi, M. et al. Footprinting of mammalian promoters: use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level. Nucleic Acids Res. 33, e176 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Gottschling, D. E. Telomere-proximal DNA in Saccharomyces cerevisiae is refractory to methyltransferase activity in vivo. Proc. Natl Acad. Sci. USA 89, 4062–4065 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Singh, J. & Klar, A. J. Active genes in budding yeast display enhanced in vivo accessibility to foreign DNA methylases: a novel in vivo probe for chromatin structure of yeast. Genes Dev. 6, 186–196 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Bell, O. et al. Accessibility of the Drosophila genome discriminates PcG repression, H4K16 acetylation and replication timing. Nature Struct. Mol. Biol. 17, 894–900 (2010).

    Article  CAS  Google Scholar 

  31. Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science 295, 1306–1311 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Tolhuis, B., Palstra, R. J., Splinter, E., Grosveld, F. & de Laat, W. Looping and interaction between hypersensitive sites in the active β-globin locus. Mol. Cell 10, 1453–1465 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Dostie, J. et al. Chromosome conformation capture carbon copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res. 16, 1299–1309 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fullwood, M. J. et al. An oestrogen-receptor-α-bound human chromatin interactome. Nature 462, 58–64 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Simonis, M. et al. Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nature Genet. 38, 1348–1354 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Tiwari, V. K., Cope, L., McGarvey, K. M., Ohm, J. E. & Baylin, S. B. A novel 6C assay uncovers Polycomb-mediated higher order chromatin conformations. Genome Res. 18, 1171–1179 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhao, Z. et al. Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nature Genet. 38, 1341–1347 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Wu, C., Wong, Y. C. & Elgin, S. C. The chromatin structure of specific genes: II. Disruption of chromatin structure during gene activity. Cell 16, 807–814 (1979).

    Article  CAS  PubMed  Google Scholar 

  39. Workman, J. L. Nucleosome displacement in transcription. Genes Dev. 20, 2009–2017 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Han, M. & Grunstein, M. Nucleosome loss activates yeast downstream promoters in vivo. Cell 55, 1137–1145 (1988).

    Article  CAS  PubMed  Google Scholar 

  41. Knezetic, J. A. & Luse, D. S. The presence of nucleosomes on a DNA template prevents initiation by RNA polymerase II in vitro. Cell 45, 95–104 (1986).

    Article  CAS  PubMed  Google Scholar 

  42. Drew, H. R. & Travers, A. A. DNA bending and its relation to nucleosome positioning. J. Mol. Biol. 186, 773–790 (1985).

    Article  CAS  PubMed  Google Scholar 

  43. Satchwell, S. C., Drew, H. R. & Travers, A. A. Sequence periodicities in chicken nucleosome core DNA. J. Mol. Biol. 191, 659–675 (1986).

    Article  CAS  PubMed  Google Scholar 

  44. Struhl, K. Naturally occurring poly(dA-dT) sequences are upstream promoter elements for constitutive transcription in yeast. Proc. Natl Acad. Sci. USA 82, 8419–8423 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Valouev, A. et al. A high-resolution, nucleosome position map of C. elegans reveals a lack of universal sequence-dictated positioning. Genome Res. 18, 1051–1063 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang, Z. et al. A packing mechanism for nucleosome organization reconstituted across a eukaryotic genome. Science 332, 977–980 (2011). The authors showed that in vitro reconstitution of nucleosome positioning outside budding yeast promoters relies mostly on ATP-dependent remodelling rather than sequence determinants.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li, B., Carey, M. & Workman, J. L. The role of chromatin during transcription. Cell 128, 707–719 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Workman, J. L. & Kingston, R. E. Nucleosome core displacement in vitro via a metastable transcription factor-nucleosome complex. Science 258, 1780–1784 (1992).

    Article  CAS  PubMed  Google Scholar 

  49. Fascher, K. D., Schmitz, J. & Horz, W. Role of trans-activating proteins in the generation of active chromatin at the PHO5 promoter in S. cerevisiae. EMBO J. 9, 2523–2528 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lomvardas, S. & Thanos, D. Nucleosome sliding via TBP DNA binding in vivo. Cell 106, 685–696 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. John, S. et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nature Genet. 43, 264–268 (2011). This genome-wide study revealed that tissue-specific DNA binding of glucorticoid receptors is largely directed by pre-existing foci of accessible chromatin.

    Article  CAS  PubMed  Google Scholar 

  52. Bucceri, A., Kapitza, K. & Thoma, F. Rapid accessibility of nucleosomal DNA in yeast on a second time scale. EMBO J. 25, 3123–3132 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li, G., Levitus, M., Bustamante, C. & Widom, J. Rapid spontaneous accessibility of nucleosomal DNA. Nature Struct. Mol. Biol. 12, 46–53 (2005).

    Article  CAS  Google Scholar 

  54. Almer, A. & Horz, W. Nuclease hypersensitive regions with adjacent positioned nucleosomes mark the gene boundaries of the PHO5/PHO3 locus in yeast. EMBO J. 5, 2681–2687 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lam, F. H., Steger, D. J. & O'Shea, E. K. Chromatin decouples promoter threshold from dynamic range. Nature 453, 246–250 (2008). This study systematically dissects the interplay between affinity and location of transcription factor binding sites relative to positioned nucleosomes and implies a role for chromatin to fine-tune the transcriptional response to external signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Clapier, C. R. & Cairns, B. R. The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 78, 273–304 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Becker, P. B. & Horz, W. ATP-dependent nucleosome remodeling. Annu. Rev. Biochem. 71, 247–273 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Parnell, T. J., Huff, J. T. & Cairns, B. R. RSC regulates nucleosome positioning at Pol II genes and density at Pol III genes. EMBO J. 27, 100–110 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Hartley, P. D. & Madhani, H. D. Mechanisms that specify promoter nucleosome location and identity. Cell 137, 445–458 (2009). This work dissects the order of events and reveals concerted action of sequence determinants, transcription-factor binding and nucleosome remodelling that lead to establishment of NDRs in budding yeast.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Raisner, R. M. et al. Histone variant H2A.Z marks the 5′ ends of both active and inactive genes in euchromatin. Cell 123, 233–248 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Whitehouse, I., Rando, O. J., Delrow, J. & Tsukiyama, T. Chromatin remodelling at promoters suppresses antisense transcription. Nature 450, 1031–1035 (2007). This genome-wide localization study showed that the chromatin remodeller Isw2 slides nucleosomes onto unfavourable A/T-rich sequences, which prevents aberrant transcription from canonical and cryptic start sites.

    Article  CAS  PubMed  Google Scholar 

  62. Izban, M. G. & Luse, D. S. Transcription on nucleosomal templates by RNA polymerase II in vitro: inhibition of elongation with enhancement of sequence-specific pausing. Genes Dev. 5, 683–696 (1991).

    Article  CAS  PubMed  Google Scholar 

  63. Lee, C. K., Shibata, Y., Rao, B., Strahl, B. D. & Lieb, J. D. Evidence for nucleosome depletion at active regulatory regions genome-wide. Nature Genet. 36, 900–905 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Belotserkovskaya, R. et al. FACT facilitates transcription-dependent nucleosome alteration. Science 301, 1090–1093 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Schwabish, M. A. & Struhl, K. Asf1 mediates histone eviction and deposition during elongation by RNA polymerase II. Mol. Cell 22, 415–422 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Bortvin, A. & Winston, F. Evidence that Spt6p controls chromatin structure by a direct interaction with histones. Science 272, 1473–1476 (1996).

    Article  CAS  PubMed  Google Scholar 

  67. Kaplan, C. D., Laprade, L. & Winston, F. Transcription elongation factors repress transcription initiation from cryptic sites. Science 301, 1096–1099 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Mason, P. B. & Struhl, K. The FACT complex travels with elongating RNA polymerase II and is important for the fidelity of transcriptional initiation in vivo. Mol. Cell. Biol. 23, 8323–8333 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McKittrick, E., Gafken, P. R., Ahmad, K. & Henikoff, S. Histone H3.3 is enriched in covalent modifications associated with active chromatin. Proc. Natl Acad. Sci. USA 101, 1525–1530 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schwartz, B. E. & Ahmad, K. Transcriptional activation triggers deposition and removal of the histone variant H3.3. Genes Dev. 19, 804–814 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wirbelauer, C., Bell, O. & Schubeler, D. Variant histone H3.3 is deposited at sites of nucleosomal displacement throughout transcribed genes while active histone modifications show a promoter-proximal bias. Genes Dev. 19, 1761–1766 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhang, H., Roberts, D. N. & Cairns, B. R. Genome-wide dynamics of Htz1, a histone H2A variant that poises repressed/basal promoters for activation through histone loss. Cell 123, 219–231 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jin, C. et al. H3.3/H2A.Z double variant-containing nucleosomes mark 'nucleosome-free regions' of active promoters and other regulatory regions. Nature Genet. 41, 941–945 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Rando, O. J. Global patterns of histone modifications. Curr. Opin. Genet. Dev. 17, 94–99 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Taverna, S. D., Li, H., Ruthenburg, A. J., Allis, C. D. & Patel, D. J. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nature Struct. Mol. Biol. 14, 1025–1040 (2007).

    Article  CAS  Google Scholar 

  76. Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Dorigo, B., Schalch, T., Bystricky, K. & Richmond, T. J. Chromatin fiber folding: requirement for the histone H4 N-terminal tail. J. Mol. Biol. 327, 85–96 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006). The authors provide in vitro evidence that H4K16ac antagonizes chromatin condensation by disrupting charge-based histone interactions and binding of the chromatin remodelling factor ACF.

    Article  CAS  PubMed  Google Scholar 

  79. Akhtar, A. & Becker, P. B. Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol. Cell 5, 367–375 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Larschan, E. et al. X chromosome dosage compensation via enhanced transcriptional elongation in Drosophila. Nature 471, 115–118 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Fierz, B. et al. Histone H2B ubiquitylation disrupts local and higher-order chromatin compaction. Nature Chem. Biol. 7, 113–119 (2011).

    Article  CAS  Google Scholar 

  82. Heitz, E. Das Heterochromatin der Moose. Jahrbücher für wissenschaftliche Botanik 69, 762–818 (1928).

    Google Scholar 

  83. Huisinga, K. L., Brower-Toland, B. & Elgin, S. C. The contradictory definitions of heterochromatin: transcription and silencing. Chromosoma 115, 110–122 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Schotta, G. et al. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 18, 1251–1262 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Matsui, T. et al. Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464, 927–931 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Nielsen, S. J. et al. Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561–565 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Schultz, D. C., Ayyanathan, K., Negorev, D., Maul, G. G. & Rauscher, F. J. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 16, 919–932 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D. & Grewal, S. I. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292, 110–113 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Lu, X. et al. The effect of H3K79 dimethylation and H4K20 trimethylation on nucleosome and chromatin structure. Nature Struct. Mol. Biol. 15, 1122–1124 (2008).

    Article  CAS  Google Scholar 

  92. Beisel, C. & Paro, R. Silencing chromatin: comparing modes and mechanisms. Nature Rev. Genet. 12, 123–135 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Muller, J. et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197–208 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Stock, J. K. et al. Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nature Cell Biol. 9, 1428–1435 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Francis, N. J., Kingston, R. E. & Woodcock, C. L. Chromatin compaction by a polycomb group protein complex. Science 306, 1574–1577 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Lanzuolo, C., Roure, V., Dekker, J., Bantignies, F. & Orlando, V. Polycomb response elements mediate the formation of chromosome higher-order structures in the bithorax complex. Nature Cell Biol. 9, 1167–1174 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Eskeland, R. et al. Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination. Mol. Cell 38, 452–464 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Filion, G. J. et al. Systematic protein location mapping reveals five principal chromatin types in Drosophila cells. Cell 143, 212–224 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Schwaiger, M. & Schubeler, D. A question of timing: emerging links between transcription and replication. Curr. Opin. Genet. Dev. 16, 177–183 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Gilbert, D. M. Evaluating genome-scale approaches to eukaryotic DNA replication. Nature Rev. Genet. 11, 673–684 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Gilbert, D. M. In search of the holy replicator. Nature Rev. Mol. Cell Biol. 5, 848–855 (2004).

    Article  CAS  Google Scholar 

  104. Eaton, M. L. et al. Chromatin signatures of the Drosophila replication program. Genome Res. 21, 164–174 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Cadoret, J. C. et al. Genome-wide studies highlight indirect links between human replication origins and gene regulation. Proc. Natl Acad. Sci. USA 105, 15837–15842 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Eaton, M. L., Galani, K., Kang, S., Bell, S. P. & MacAlpine, D. M. Conserved nucleosome positioning defines replication origins. Genes Dev. 24, 748–753 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Schwaiger, M. et al. Chromatin state marks cell-type- and gender-specific replication of the Drosophila genome. Genes Dev. 23, 589–601 (2009). This study shows that chromosome-wide changes in acetylation correlate more closely with advanced replication timing rather than with changes in transcription, supporting a chromatin-based regulation of the replication program.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hiratani, I. et al. Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol. 6, e245 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Mechali, M. Eukaryotic DNA replication origins: many choices for appropriate answers. Nature Rev. Mol. Cell Biol. 11, 728–738 (2010).

    Article  CAS  Google Scholar 

  110. Aboussekhra, A. et al. Mammalian DNA nucleotide excision repair reconstituted with purified protein components. Cell 80, 859–868 (1995).

    Article  CAS  PubMed  Google Scholar 

  111. Thoma, F. Repair of UV lesions in nucleosomes — intrinsic properties and remodeling. DNA Repair (Amst.) 4, 855–869 (2005).

    Article  CAS  Google Scholar 

  112. Nag, R. & Smerdon, M. J. Altering the chromatin landscape for nucleotide excision repair. Mutat. Res. 682, 13–20 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Huang, J. C. & Sancar, A. Determination of minimum substrate size for human excinuclease. J. Biol. Chem. 269, 19034–19040 (1994).

    Article  CAS  PubMed  Google Scholar 

  114. Ura, K. et al. ATP-dependent chromatin remodeling facilitates nucleotide excision repair of UV-induced DNA lesions in synthetic dinucleosomes. EMBO J. 20, 2004–2014 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. van Attikum, H. & Gasser, S. M. The histone code at DNA breaks: a guide to repair? Nature Rev. Mol. Cell Biol. 6, 757–765 (2005).

    Article  CAS  Google Scholar 

  116. Gong, F., Fahy, D. & Smerdon, M. J. Rad4-Rad23 interaction with SWI/SNF links ATP-dependent chromatin remodeling with nucleotide excision repair. Nature Struct. Mol. Biol. 13, 902–907 (2006).

    Article  CAS  Google Scholar 

  117. Zhang, L., Zhang, Q., Jones, K., Patel, M. & Gong, F. The chromatin remodeling factor BRG1 stimulates nucleotide excision repair by facilitating recruitment of XPC to sites of DNA damage. Cell Cycle 8, 3953–3959 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Zhao, Q. et al. Modulation of nucleotide excision repair by mammalian SWI/SNF chromatin-remodeling complex. J. Biol. Chem. 284, 30424–30432 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jiang, Y. et al. INO80 chromatin remodeling complex promotes the removal of UV lesions by the nucleotide excision repair pathway. Proc. Natl Acad. Sci. USA 107, 17274–17279 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yasuda, T. et al. Nucleosomal structure of undamaged DNA regions suppresses the non-specific DNA binding of the XPC complex. DNA Repair (Amst.) 4, 389–395 (2005).

    Article  CAS  Google Scholar 

  121. Groisman, R. et al. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113, 357–367 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Sugasawa, K. et al. UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex. Cell 121, 387–400 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Scrima, A. et al. Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex. Cell 135, 1213–1223 (2008). This study showed the mechanism of UV-damage recognition by the UV-DDB complex. A model is presented whereby damage recognition is compatible with chromatin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wang, H. et al. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol. Cell 22, 383–394 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Elgin, J. Crabtree and members of the Crabtree and Schübeler laboratories for their insightful comments on the manuscript. O.B. is supported by a Human Frontier Science Program fellowship. V.K.T. is supported by a Marie Curie International Incoming Fellowship (IIF) and a European Molecular Biology Organisation (EMBO) long-term postdoctoral fellowship. Research in the laboratory of D.S. and N.T. is supported by the Novartis Research Foundation. The laboratory of D.S. is supported by the European Union (Network of Excellence 'The Epigenome' LSHG-CT-2004-503433, LSHG-CT-2006-037415), the European Research Council (ERC-204264) and SystemsX.ch, the Swiss initiative in Systems Biology. Research in the laboratory of N.T. is supported by grants from the European Research Council (ERC-2010-StG 260481-MoBa-CS), Association of International Cancer Research (AICR10-0292), OncoSuisse (OCS-02365-02-2009) and the Swiss National Foundation (31003A_120205). We apologize to those colleagues whose work we could not mention owing to space limitations.

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Glossary

Linker histones

Linker histones are not part of the nucleosomal core but, at least in the case of the linker histone H1, bind to DNA adjacent to the octamer.

Thermal motion

In the context of nucleosomes, in vitro experiments under physiological salt conditions revealed that higher temperatures, especially at 37°C, promote short-range movement (that is, tens of base pairs) of nucleosomes in cis.

Nucleosome occupancy

The probability that a genomic site is covered by a histone octamer; this is an average frequency measure in a cell population.

Chromatin immunoprecipitation followed by microarray

(ChIP–chip). This is a technique that combines chromatin immunoprecipitation (ChIP) with detection on microarrays ('chip') to comprehensively investigate the distribution of a protein of interest. Protein–DNA complexes are immunoprecipitated and, after isolation, bound DNA sequences can be detected by hybridization to probes on a microarray chip.

Chromatin immunoprecipitation followed by sequencing

(ChIP–seq). An advancement of chromatin immunoprecipitation followed by microarray (ChIP–chip), ChIP–seq combines ChIP with massively parallel DNA sequencing to identify binding sites of a protein of interest genome-wide.

DNase I hypersensitive sites

Chromatin regions with frequent cleavage by DNase I. DNase I hypersensitivity generally reflects a local reduction in nucleosome occupancy.

Nucleosome positioning

This can describe either the rotational or translational orientation of the DNA around the histone octamer. Rotational positioning describes the orientation of the DNA helix on the surface of the histone octamer. Translational nucleosome positioning relates to the specific 146 bp of genomic DNA covered by the histone octamer. A highly positioned nucleosome is one that covers the same sequence in most cells within a population.

Bisulphite treatment

Treatment of DNA with bisulphite chemically converts unmethylated cytosines to uracil. As methylated cytosines are unaffected, the location of methylation can be identified by sequencing the bisulphite-treated DNA.

Fluorescence in situ hybridization

(FISH). A technique that can be used to visualize the location of DNA sequences within the nucleus by using sequence-specific fluorescent probes and microscopy.

Chromosome conformation capture

(3C). A technique used to study the spatial organization of chromosomal regions in vivo, based on the ligation of DNA elements that are in close physical proximity.

Nucleosome-depleted regions

(NDRs). Sites of reduced nucleosome occupancy compared to immediate surrounding regions. NDRs are frequently located at the beginning and end of genes, harbour cis- regulatory binding sites and display sensitivity to DNase I and formaldehyde-assisted isolation of regulatory elements (FAIRE) detection.

RSC

A multi-subunit chromatin remodelling complex that uses DNA-dependent ATP hydrolysis to catalyse nucleosome mobilization at active genes.

Chromatin remodelling

Enzyme-assisted histone or nucleosome mobilization, which requires ATP hydrolysis. ATP-dependent chromatin remodelling influences local chromatin structure to facilitate or prevent protein accessibility, which is required to initiate DNA-templated reactions.

FACT

Stands for 'facilitates chromatin transcription' and is a chromatin-specific histone chaperone that is required for transcriptional elongation through chromatin templates.

PHD domains

Derived from the name 'plant homeodomain', these protein domains were initially discovered as a Cys4-His-Cys3 motif in the homeodomain protein HAT3 in Arabidopsis thaliana. They are present in many proteins, several of which are nuclear and involved in chromatin-mediated gene regulation.

30 nm fibres

An array of nucleosomes (often called 'beads on a string') wraps into a more condensed fibre, which has a diameter of 30 nm. A simple 30 nm fibre has been reconstituted in vitro, but its actual composition in vivo remains unclear.

Constitutive heterochromatin

Genomic regions, predominantly at centromeres and telomeres, which remain condensed throughout the cell cycle. These often consist of highly condensed, repetitive DNA and are largely transcriptionally silent.

Polycomb group proteins

An evolutionarily conserved set of proteins that regulate the temporal and spatial expression pattern of key developmental genes through modulation of chromatin structure.

Origin-recognition complex

A multi-subunit protein complex that binds to origins of replication and that is essential for initiation of replication.

Nucleotide excision repair

A versatile repair pathway that is involved in the removal of the most bulky DNA lesions, such as UV-induced thymine dimers and 6–4 photoproducts. If left unrepaired, these lesions stall transcription and can only be repaired through potentially error-prone translesion polymerases. Mutations in this pathway result in premature ageing syndromes, as well as cancer predisposition.

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Bell, O., Tiwari, V., Thomä, N. et al. Determinants and dynamics of genome accessibility. Nat Rev Genet 12, 554–564 (2011). https://doi.org/10.1038/nrg3017

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