The molecular hallmarks of epigenetic control

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Abstract

Over the past 20 years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms that alter chromatin in response to physiological or pathological signals have transformed our knowledge of epigenetics from a collection of curious biological phenomena to a functionally dissected research field. Here, we provide a personal perspective on the development of epigenetics, from its historical origins to what we define as 'the modern era of epigenetic research'. We primarily highlight key molecular mechanisms of and conceptual advances in epigenetic control that have changed our understanding of normal and perturbed development.

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Figure 1: Euchromatin and heterochromatin.
Figure 2: Timeline of major discoveries and advances in epigenetic research between 1996 and 2016.
Figure 3: Key examples of chromatin contribution to epigenome function.
Figure 4: Molecular hallmarks of epigenetic control and examples for their medical relevance, together with possible therapeutic modulation.

References

  1. 1

    Waddington, C. H. The epigenotype. Endeavour 1, 18–20 (1942).

  2. 2

    Waddington, C. H. Canalization of development and the inheritance of acquired characters. Nature 150, 563–565 (1942).

  3. 3

    Allis, C. D., Caparros, M., Jenuwein, T. & Reinberg, D. (eds) Epigenetics 2nd edn (Cold Spring Harbor Laboratory Press, 2015).

  4. 4

    Heitz, E. Das Heterochromatin der Moose. Jahrb. Wiss. Bot. 69, 762–818 (1928).

  5. 5

    Muller, H. J. & Altenburg, E. The frequency of translocations produced by X-rays in Drosophila. Genetics 15, 283–311 (1930).

  6. 6

    McClintock, B. Chromosome organization and genic expression. Cold Spring Harb. Symp. Quant. Biol. 16, 13–47 (1951).

  7. 7

    Lyon, M. F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373 (1961).

  8. 8

    Surani, M. A., Barton, S. C. & Norris, M. L. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308, 548–550 (1984).

  9. 9

    McGrath, J. & Solter, D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37, 179–183 (1984).

  10. 10

    Hotchkiss, R. D. The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J. Biol. Chem. 175, 315–332 (1948).

  11. 11

    Holliday, R. & Pugh, J. E. DNA modification mechanisms and gene activity during development. Science 187, 226–232 (1975).

  12. 12

    Razin, A. & Riggs, A. D. DNA methylation and gene function. Science 210, 604–610 (1980).

  13. 13

    Bird, A., Taggart, M., Frommer, M., Miller, O. J. & Macleod, D. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40, 91–99 (1985).

  14. 14

    Taylor, S. M. & Jones, P. A. Multiple new phenotypes induced in 10T1/2 and 3T3 cells treated with 5-azacytidine. Cell 17, 771–779 (1979).

  15. 15

    Feinberg, A. P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 (1983).

  16. 16

    Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nat. Rev. Cancer 4, 143–153 (2004).

  17. 17

    Gruenbaum, Y., Cedar, H. & Razin, A. Substrate and sequence specificity of a eukaryotic DNA methylase. Nature 295, 620–622 (1982).

  18. 18

    Bestor, T. H. & Ingram, V. M. Two DNA methyltransferases from murine erythroleukemia cells: purification, sequence specificity, and mode of interaction with DNA. Proc. Natl Acad. Sci. USA 80, 5559–5563 (1983).

  19. 19

    Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

  20. 20

    Meehan, R. R., Lewis, J. D., McKay, S., Kleiner, E. L. & Bird, A. P. Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58, 499–507 (1989).

  21. 21

    Olins, D. E. & Olins, A. L. Chromatin history: our view from the bridge. Nat. Rev. Mol. Cell Biol. 4, 809–814 (2003).

  22. 22

    Kornberg, R. D. Chromatin structure: a repeating unit of histones and DNA. Science 184, 868–871 (1974).

  23. 23

    Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997).

  24. 24

    Allfrey, V. G., Faulkner, R. & Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl Acad. Sci. USA 51, 786–794 (1964).

  25. 25

    Verdin, E. & Ott, M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat. Rev. Mol. Cell Biol. 16, 258–264 (2015).

  26. 26

    Kayne, P. S. et al. Extremely conserved histone H4 N terminus is dispensable for growth but essential for repressing the silent mating loci in yeast. Cell 55, 27–39 (1988).

  27. 27

    Megee, P. C., Morgan, B. A., Mittman, B. A. & Smith, M. M. Genetic analysis of histone H4: essential role of lysines subject to reversible acetylation. Science 247, 841–845 (1990).

  28. 28

    Jeppesen, P. & Turner, B. M. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression. Cell 74, 281–289 (1993).

  29. 29

    Braunstein, M., Sobel, R. E., Allis, C. D., Turner, B. M. & Broach, J. R. Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Mol. Cell. Biol. 16, 4349–4356 (1996).

  30. 30

    Bone, J. R. et al. Acetylated histone H4 on the male X chromosome is associated with dosage compensation in Drosophila. Genes Dev. 8, 96–104 (1994).

  31. 31

    Hebbes, T. R., Clayton, A. L., Thorne, A. W. & Crane-Robinson, C. Core histone hyperacetylation co-maps with generalized DNase I sensitivity in the chicken β-globin chromosomal domain. EMBO J. 13, 1823–1830 (1994).

  32. 32

    Elgin, S. C. & Reuter, G. Position-effect variegation, heterochromatin formation, and gene silencing in Drosophila. Cold Spring Harb. Perspect. Biol. 5, a017780 (2013).

  33. 33

    Grossniklaus, U. & Paro, R. Transcriptional silencing by Polycomb-group proteins. Cold Spring Harb. Perspect. Biol. 6, a019331 (2014).

  34. 34

    Kingston, R. E. & Tamkun, J. W. Transcriptional regulation by trithorax-group proteins. Cold Spring Harb. Perspect. Biol. 6, a019349 (2014).

  35. 35

    Grunstein, M. & Gasser, S. M. Epigenetics in Saccharomyces cerevisiae. Cold Spring Harb. Perspect. Biol. 5, a017491 (2013).

  36. 36

    Allshire, R. C. & Ekwall, K. Epigenetic regulation of chromatin states in Schizosaccharomyces pombe. Cold Spring Harb. Perspect. Biol. 7, a018770 (2015).

  37. 37

    Pikaard, C. S. & Mittelsten Scheid, O. Epigenetic regulation in plants. Cold Spring Harb. Perspect. Biol. 6, a019315 (2014).

  38. 38

    Brownell, J. E. et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84, 843–851 (1996).

  39. 39

    Kleff, S., Andrulis, E. D., Anderson, C. W. & Sternglanz, R. Identification of a gene encoding a yeast histone H4 acetyltransferase. J. Biol. Chem. 270, 24674–24677 (1995).

  40. 40

    Parthun, M. R., Widom, J. & Gottschling, D. E. The major cytoplasmic histone acetyltransferase in yeast: links to chromatin replication and histone metabolism. Cell 87, 85–94 (1996).

  41. 41

    Kuo, M. H. et al. Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines. Nature 383, 269–272 (1996).

  42. 42

    Mizzen, C. A. et al. The TAF(II)250 subunit of TFIID has histone acetyltransferase activity. Cell 87, 1261–1270 (1996).

  43. 43

    Yang, X. J., Ogryzko, V. V., Nishikawa, J., Howard, B. H. & Nakatani, Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382, 319–324 (1996).

  44. 44

    Ogryzko, V. V., Schiltz, R. L., Russanova, V., Howard, B. H. & Nakatani, Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87, 953–959 (1996).

  45. 45

    Bannister, A. J. & Kouzarides, T. The CBP co-activator is a histone acetyltransferase. Nature 384, 641–643 (1996).

  46. 46

    Marmorstein, R. & Zhou, M. M. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb. Perspect. Biol. 6, a018762 (2014).

  47. 47

    Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996).

  48. 48

    Seto, E. & Yoshida, M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6, a018713 (2014).

  49. 49

    Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

  50. 50

    Berger, S. L. & Sassone-Corsi, P. Metabolic signaling to chromatin. Cold Spring Harb. Perspect. Biol. http://dx.doi.org/10.1101/cshperspect.a019463 (2016).

  51. 51

    Dhalluin, C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496 (1999).

  52. 52

    Patel, D. J. A structural perspective on readout of epigenetic histone and DNA methylation marks. Cold Spring Harb. Perspect. Biol. 8, a018754 (2015).

  53. 53

    Tschiersch, B. et al. The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes. EMBO J. 13, 3822–3831 (1994).

  54. 54

    Aagaard, L. et al. Functional mammalian homologues of the Drosophila PEV-modifier Su(var)3-9 encode centromere-associated proteins which complex with the heterochromatin component M31. EMBO J. 18, 1923–1938 (1999).

  55. 55

    Jenuwein, T., Laible, G., Dorn, R. & Reuter, G. SET domain proteins modulate chromatin domains in eu- and heterochromatin. Cell. Mol. Life Sci. 54, 80–93 (1998).

  56. 56

    Melcher, M. et al. Structure-function analysis of SUV39H1 reveals a dominant role in heterochromatin organization, chromosome segregation, and mitotic progression. Mol. Cell. Biol. 20, 3728–3741 (2000).

  57. 57

    Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

  58. 58

    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).

  59. 59

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

  60. 60

    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).

  61. 61

    Paik, W. K. & Kim, S. Protein methylation. Science 174, 114–119 (1971).

  62. 62

    Li, E. & Zhang, Y. DNA methylation in mammals. Cold Spring Harb. Perspect. Biol. 6, a019133 (2014).

  63. 63

    Cheng, X. Structural and functional coordination of DNA and histone methylation. Cold Spring Harb. Perspect. Biol. 6, a018747 (2014).

  64. 64

    Tachibana, M., Sugimoto, K., Fukushima, T. & Shinkai, Y. SET domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem. 276, 25309–25317 (2001).

  65. 65

    Czermin, B. et al. Drosophila Enhancer of zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185–196 (2002).

  66. 66

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

  67. 67

    Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of zeste protein. Genes Dev. 16, 2893–2905 (2002).

  68. 68

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

  69. 69

    Krogan, N. J. et al. COMPASS, a histone H3 (lysine 4) methyltransferase required for telomeric silencing of gene expression. J. Biol. Chem. 277, 10753–10755 (2002).

  70. 70

    Milne, T. A. et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol. Cell 10, 1107–1117 (2002).

  71. 71

    Nakamura, T. et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol. Cell 10, 1119–1128 (2002).

  72. 72

    Yokoyama, A. et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol. Cell. Biol. 24, 5639–5649 (2004).

  73. 73

    Dou, Y. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat. Struct. Mol. Biol. 13, 713–719 (2006).

  74. 74

    Heard, E. et al. Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell 107, 727–738 (2001).

  75. 75

    Peters, A. H. et al. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nat. Genet. 30, 77–80 (2002).

  76. 76

    Peters, A. H. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577–1589 (2003).

  77. 77

    Rice, J. C. et al. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol. Cell 12, 1591–1598 (2003).

  78. 78

    Plath, K. et al. Role of histone H3 lysine 27 methylation in X inactivation. Science 300, 131–135 (2003).

  79. 79

    van Leeuwen, F., Gafken, P. R. & Gottschling, D. E. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745–756 (2002).

  80. 80

    Chen, D. et al. Regulation of transcription by a protein methyltransferase. Science 284, 2174–2177 (1999).

  81. 81

    Wang, H. et al. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293, 853–857 (2001).

  82. 82

    Bauer, U. M., Daujat, S., Nielsen, S. J., Nightingale, K. & Kouzarides, T. Methylation at arginine 17 of histone H3 is linked to gene activation. EMBO Rep. 3, 39–44 (2002).

  83. 83

    Ushijima, T. Cancer epigenetics: now harvesting fruit and seeding for common diseases. Biochem. Biophys. Res. Commun. 455, 1–2 (2014).

  84. 84

    Turner, B. M. Decoding the nucleosome. Cell 75, 5–8 (1993).

  85. 85

    Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

  86. 86

    Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

  87. 87

    Fischle, W., Wang, Y. & Allis, C. D. Binary switches and modification cassettes in histone biology and beyond. Nature 425, 475–479 (2003).

  88. 88

    Ruthenburg, A. J., Li, H., Patel, D. J. & Allis, C. D. Multivalent engagement of chromatin modifications by linked binding modules. Nat. Rev. Mol. Cell Biol. 8, 983–994 (2007).

  89. 89

    Schreiber, S. L. & Bernstein, B. E. Signaling network model of chromatin. Cell 111, 771–778 (2002).

  90. 90

    Jones, P. L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19, 187–191 (1998).

  91. 91

    Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).

  92. 92

    Tamaru, H. & Selker, E. U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001).

  93. 93

    Jackson, J. P., Lindroth, A. M., Cao, X. & Jacobsen, S. E. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416, 556–560 (2002).

  94. 94

    Ooi, S. K. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714–717 (2007).

  95. 95

    Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).

  96. 96

    Cedar, H. & Bergman, Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat. Rev. Genet. 10, 295–304 (2009).

  97. 97

    Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).

  98. 98

    Thomson, J. P. et al. CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 464, 1082–1086 (2010).

  99. 99

    Blackledge, N. P. et al. CpG islands recruit a histone H3 lysine 36 demethylase. Mol. Cell 38, 179–190 (2010).

  100. 100

    Domcke, S. et al. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature 528, 575–579 (2015).

  101. 101

    Hall, I. M. et al. Establishment and maintenance of a heterochromatin domain. Science 297, 2232–2237 (2002).

  102. 102

    Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine 9 methylation by RNAi. Science 297, 1833–1837 (2002).

  103. 103

    Taverna, S. D., Coyne, R. S. & Allis, C. D. Methylation of histone H3 at lysine 9 targets programmed DNA elimination in Tetrahymena. Cell 110, 701–711 (2002).

  104. 104

    Mochizuki, K., Fine, N. A., Fujisawa, T. & Gorovsky, M. A. Analysis of a piwi-related gene implicates small RNAs in genome rearrangement in Tetrahymena. Cell 110, 689–699 (2002).

  105. 105

    Martienssen, R. & Moazed, D. RNAi and heterochromatin assembly. Cold Spring Harb. Perspect. Biol. 7, a019323 (2015).

  106. 106

    Chalker, D. L., Meyer, E. & Mochizuki, K. Epigenetics of ciliates. Cold Spring Harb. Perspect. Biol. 5, a017764 (2013).

  107. 107

    Reyes-Turcu, F. E., Zhang, K., Zofall, M., Chen, E. & Grewal, S. I. Defects in RNA quality control factors reveal RNAi-independent nucleation of heterochromatin. Nat. Struct. Mol. Biol. 18, 1132–1138 (2011).

  108. 108

    Hirschhorn, J. N., Brown, S. A., Clark, C. D. & Winston, F. Evidence that SNF2/SWI2 and SNF5 activate transcription in yeast by altering chromatin structure. Genes Dev. 6, 2288–2298 (1992).

  109. 109

    Cote, J., Quinn, J., Workman, J. L. & Peterson, C. L. Stimulation of GAL4 derivative binding to nucleosomal DNA by the yeast SWI/SNF complex. Science 265, 53–60 (1994).

  110. 110

    Kwon, H., Imbalzano, A. N., Khavari, P. A., Kingston, R. E. & Green, M. R. Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature 370, 477–481 (1994).

  111. 111

    Tsukiyama, T. & Wu, C. Purification and properties of an ATP-dependent nucleosome remodeling factor. Cell 83, 1011–1020 (1995).

  112. 112

    Ito, T., Bulger, M., Pazin, M. J., Kobayashi, R. & Kadonaga, J. T. ACF, an ISWI-containing and ATP-utilizing chromatin assembly and remodeling factor. Cell 90, 145–155 (1997).

  113. 113

    Varga-Weisz, P. D. et al. Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II. Nature 388, 598–602 (1997).

  114. 114

    Lorch, Y., Cairns, B. R., Zhang, M. & Kornberg, R. D. Activated RSC-nucleosome complex and persistently altered form of the nucleosome. Cell 94, 29–34 (1998).

  115. 115

    Becker, P. B. & Workman, J. L. Nucleosome remodeling and epigenetics. Cold Spring Harb. Perspect. Biol. 5, a017905 (2013).

  116. 116

    Kadoch, C. & Crabtree, G. R. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci. Adv. 1, e1500447 (2015).

  117. 117

    Henikoff, S. & Smith, M. M. Histone variants and epigenetics. Cold Spring Harb. Perspect. Biol. 7, a019364 (2015).

  118. 118

    Ahmad, K. & Henikoff, S. The histone variant H3.3 marks active chromatin by replication-independent nucleosome assembly. Mol. Cell 9, 1191–1200 (2002).

  119. 119

    Tagami, H., Ray-Gallet, D., Almouzni, G. & Nakatani, Y. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116, 51–61 (2004).

  120. 120

    Smith, S. & Stillman, B. Purification and characterization of CAF-I, a human cell factor required for chromatin assembly during DNA replication in vitro. Cell 58, 15–25 (1989).

  121. 121

    Mizuguchi, G. et al. ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex. Science 303, 343–348 (2004).

  122. 122

    Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

  123. 123

    Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).

  124. 124

    Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

  125. 125

    Fodor, B. D. et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006).

  126. 126

    Klose, R. J. et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442, 312–316 (2006).

  127. 127

    Reik, W. & Surani, M. A. Germline and Pluripotent Stem Cells. Cold Spring Harb. Perspect. Biol. 7, a019422 (2015).

  128. 128

    Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).

  129. 129

    Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

  130. 130

    Ito, S. et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129–1133 (2010).

  131. 131

    He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).

  132. 132

    Zhao, Y. & Garcia, B. A. Comprehensive catalog of currently documented histone modifications. Cold Spring Harb. Perspect. Biol. 7, a025064 (2015).

  133. 133

    Noma, K., Allis, C. D. & Grewal, S. I. Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science 293, 1150–1155 (2001).

  134. 134

    Litt, M. D., Simpson, M., Gaszner, M., Allis, C. D. & Felsenfeld, G. Correlation between histone lysine methylation and developmental changes at the chicken β-globin locus. Science 293, 2453–2455 (2001).

  135. 135

    Kim, T. H. et al. A high-resolution map of active promoters in the human genome. Nature 436, 876–880 (2005).

  136. 136

    Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

  137. 137

    Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).

  138. 138

    Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

  139. 139

    Azuara, V. et al. Chromatin signatures of pluripotent cell lines. Nat. Cell Biol. 8, 532–538 (2006).

  140. 140

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

  141. 141

    Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

  142. 142

    Voigt, P. et al. Asymmetrically modified nucleosomes. Cell 151, 181–193 (2012).

  143. 143

    Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279–283 (2011).

  144. 144

    Roadmap Epigenomics Consortium et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).

  145. 145

    Grün, D. et al. Single-cell messenger RNA sequencing reveals rare intestinal cell types. Nature 525, 251–255 (2015).

  146. 146

    Battich, N., Stoeger, T. & Pelkmans, L. Control of transcript variability in single mammalian cells. Cell 163, 1596–1610 (2015).

  147. 147

    Morris, K. V. & Mattick, J. S. The rise of regulatory RNA. Nat. Rev. Genet. 15, 423–437 (2014).

  148. 148

    Davis, R. L., Weintraub, H. & Lassar, A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987–1000 (1987).

  149. 149

    Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

  150. 150

    Hochedlinger, K. & Jaenisch, R. Induced pluripotency and epigenetic reprogramming. Cold Spring Harb. Perspect. Biol. 7, a019448 (2015).

  151. 151

    Chen, J. et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat. Genet. 45, 34–42 (2013).

  152. 152

    Matoba, S. et al. Embryonic development following somatic cell nuclear transfer impeded by persisting histone methylation. Cell 159, 884–895 (2014).

  153. 153

    Blaschke, K. et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500, 222–226 (2013).

  154. 154

    Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).

  155. 155

    Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome. Cell 151, 994–1004 (2012).

  156. 156

    Tee, W. W. & Reinberg, D. Chromatin features and the epigenetic regulation of pluripotency states in ESCs. Development 141, 2376–2390 (2014).

  157. 157

    Gut, P. & Verdin, E. The nexus of chromatin regulation and intermediary metabolism. Nature 502, 489–498 (2013).

  158. 158

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

  159. 159

    Jones, P. A. & Baylin, S. B. Epigenetic determinants of cancer. Cold Spring Harb. Perspect. Biol. 6, a019505 (2014).

  160. 160

    Marks, P. A. Discovery and development of SAHA as an anticancer agent. Oncogene 26, 1351–1356 (2007).

  161. 161

    Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome — biological and translational implications. Nat. Rev. Cancer 11, 726–734 (2011).

  162. 162

    Chi, P., Allis, C. D. & Wang, G. G. Covalent histone modifications — miswritten, misinterpreted and miserased in human cancers. Nat. Rev. Cancer 10, 457–469 (2010).

  163. 163

    Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).

  164. 164

    Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).

  165. 165

    Pujadas, E. & Feinberg, A. P. Regulated noise in the epigenetic landscape of development and disease. Cell 148, 1123–1131 (2012).

  166. 166

    Groselj, B., Sharma, N. L., Hamdy, F. C., Kerr, M. & Kiltie, A. E. Histone deacetylase inhibitors as radiosensitisers: effects on DNA damage signaling and repair. Br. J. Cancer 108, 748–754 (2013).

  167. 167

    Zoghbi, H. Y. & Beaudet, A. L. Epigenetics and human disease. Cold Spring Harb. Perspect. Biol. 8, a019497 (2015).

  168. 168

    Audia, J. E. & Campbell, R. M. Histone modifications and cancer. Cold Spring Harb. Perspect. Biol. 8, a019521 (2015).

  169. 169

    Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).

  170. 170

    Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010).

  171. 171

    Dawson, M. A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533 (2011).

  172. 172

    Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K. & Schapira, M. Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discov. 11, 384–400 (2012).

  173. 173

    Rodriguez, R. & Miller, K. M. Unravelling the genomic targets of small molecules using high-throughput sequencing. Nat. Rev. Genet. 15, 783–796 (2014).

  174. 174

    Busslinger, M. & Tarakhovsky, A. Epigenetic control of immunity. Cold Spring Harb. Perspect. Biol. 6, a019307 (2014).

  175. 175

    Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

  176. 176

    Lara-Astiaso, D. et al. Immunogenetics: chromatin state dynamics during blood formation. Science 345, 943–949 (2014).

  177. 177

    Yoshida, K. et al. The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory. Nat. Immunol. 16, 1034–1043 (2015).

  178. 178

    Bhatt, D. M. et al. Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions. Cell 150, 279–290 (2012).

  179. 179

    Adelman, K. & Lis, J. T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat. Rev. Genet. 13, 720–731 (2012).

  180. 180

    Su, I. H. et al. Polycomb group protein Ezh2 controls actin polymerization and cell signaling. Cell 121, 425–436 (2005).

  181. 181

    Cao, K. et al. Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity. Oncogene 34, 5960–5970 (2015).

  182. 182

    Fang, T. C. et al. Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response. J. Exp. Med. 209, 661–669 (2012).

  183. 183

    Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015).

  184. 184

    Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).

  185. 185

    Glozak, M. A., Sengupta, N., Zhang, X. & Seto, E. Acetylation and deacetylation of non-histone proteins. Gene 363, 15–23 (2005).

  186. 186

    Biggar, K. K. & Li, S. S. Non-histone protein methylation as a regulator of cellular signalling and function. Nat. Rev. Mol. Cell Biol. 16, 5–17 (2015).

  187. 187

    Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

  188. 188

    Sampath, S. C. et al. Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol. Cell 27, 596–608 (2007).

  189. 189

    Marazzi, I. et al. Suppression of the antiviral response by an influenza histone mimic. Nature 483, 428–433 (2012).

  190. 190

    Almouzni, G. & Cedar, H. Maintenance of epigenetic information. Cold Spring Harb. Perspect. Biol. 8, a019372 (2015).

  191. 191

    Grewal, S. I. & Klar, A. J. Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. Cell 86, 95–101 (1996).

  192. 192

    Cavalli, G. & Paro, R. The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis. Cell 93, 505–518 (1998).

  193. 193

    Ragunathan, K., Jih, G. & Moazed, D. Epigenetic inheritance uncoupled from sequence-specific recruitment. Science 348, 6230 (2015).

  194. 194

    Audergon, P. N. et al. Restricted epigenetic inheritance of H3K9 methylation. Science 348, 132–135 (2015).

  195. 195

    Gaydos, L. J., Wang, W. & Strome, S. Gene repression. H3K27me and PRC2 transmit a memory of repression across generations and during development. Science 345, 1515–1518 (2014).

  196. 196

    Margueron, R. et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762–767 (2009).

  197. 197

    Jiao, L. & Liu, X. Structural basis of histone H3K27 trimethylation by an active Polycomb repressive complex 2. Science 350, 6258 (2015).

  198. 198

    Ost, A. et al. Paternal diet defines offspring chromatin state and intergenerational obesity. Cell 159, 1352–1364 (2014).

  199. 199

    Carone, B. R. et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084–1096 (2010).

  200. 200

    Baulcombe, D. C. & Dean, C. Epigenetic regulation in plant responses to the environment. Cold Spring Harb. Perspect. Biol. 6, a019471 (2014).

  201. 201

    Rassoulzadegan, M. et al. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 441, 469–474 (2006).

  202. 202

    Gapp, K. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17, 667–669 (2014).

  203. 203

    Siklenka, K. et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, 6261 (2015).

  204. 204

    Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016).

  205. 205

    Grün, D. & van Oudenaarden, A. Design and analysis of single-cell sequencing experiments. Cell 163, 799–810 (2015).

  206. 206

    Bickmore, W. A. & van Steensel, B. Genome architecture: domain organization of interphase chromosomes. Cell 152, 1270–1284 (2013).

  207. 207

    Dekker, J. & Misteli, T. Long-range chromatin interactions. Cold Spring Harb. Perspect. Biol. 7, a019356 (2015).

  208. 208

    Tang, Z. et al. CTCF-mediated human 3D genome architecture reveals chromatin topology for transcription. Cell 163, 1611–1627 (2015).

  209. 209

    Rinn, J. L., & Chang, H. Y. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145–166 (2012).

  210. 210

    Yan, H. et al. Eusocial insects as emerging models for behavioural epigenetics. Nat. Rev. Genet. 15, 677–688 (2014).

  211. 211

    Lempradl, A., Pospisilik, J. A. & Penninger, J. M. Exploring the emerging complexity in transcriptional regulation of energy homeostasis. Nat. Rev. Genet. 16, 665–681 (2015).

  212. 212

    Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).

  213. 213

    Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).

  214. 214

    Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).

  215. 215

    Behjati, S. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat. Genet. 45, 1479–1482 (2013).

  216. 216

    Roy, D. M., Walsh, L. A. & Chan, T. A. Driver mutations of cancer epigenomes. Protein Cell 5, 265–296 (2014).

  217. 217

    Polak, P. et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518, 360–364 (2015).

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Acknowledgements

C.D.A. and T.J. are grateful to all of our laboratory members, past and present, and to our scientific colleagues in the field for helping us 'write' the history that we review here. Their hard work, insights and passion for the field of epigenetics have made the last 20 years such an enjoyable ride. We thank P. Jones (Grand Rapids, Michigan, USA) and A. Tarakhovsky (New York, USA) for giving us feedback on this manuscript and M. Onishi-Seebacher (Freiburg, Germany) for help with the figure preparations and reference listings. Our objective in this article is to be more reflective than comprehensive, and admittedly, we have brought forward our personal views. We ask for understanding from those colleagues whose important contributions could not be explicitly mentioned.

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Correspondence to C. David Allis or Thomas Jenuwein.

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The authors declare no competing financial interests.

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Glossary

Binary switches

The modification of adjacent or nearby histone residues affecting recognition and binding by reader proteins.

Cellular reprogramming

Conversion of a differentiated cell to an embryonic state.

Charge effects

The effect of post-translational histone modifications on altering the electrostatic interaction with DNA.

Enhancer of zeste

(E(z)). Originally identified in genetic screens for homeotic transformations in Drosophila melanogaster and later shown to encode a histone H3 lysine 27 (H3K27) methylating enzyme.

Erasers

Enzymes that remove histone modifications from chromatin.

Euchromatin

Light-staining, decondensed and transcriptionally accessible regions of the genome.

Heterochromatin

Dark-staining, condensed and gene-poor regions of the genome.

Histone cassettes

Short sequences in histone proteins with clustered histone modifications that direct the biological readout in a combinatorial fashion.

Imprinting

A chromatin state defined by whether the gene or genetic locus is inherited from the male or the female germ line.

Mating-type loci

Genetic elements in yeast containing mating-type information (a or α) that is activated by recombination from heterochromatic copies of one of the two mating-type alleles.

Multivalency

A property in which several histone modifications work together to increase the binding of reader proteins or the stability of a nucleosomal arrangement.

Polycomb

Originally identified in genetic screens for homeotic transformations in Drosophila melanogaster and later shown to encode a chromodomain-containing methylated histone H3 lysine 27 (H3K27me)-binding factor.

Position-effect variegation

(PEV). Stochastic and variegated expression of a gene due to juxtaposition to heterochromatic domains.

Readers

Proteins that recognize and bind chromatin through histone modification recognition domains.

SET domain

A 120-amino-acid signature domain for histone lysine methyltransferases (KMTs) that is conserved in Suppressor of variegation 3–9, Enhancer of zeste and Trithorax.

Silent information regulator proteins

A complex of trans-acting silencing proteins involved in establishing and maintaining heterochromatin in buddingyeast.

Suppressor of variegation 3–9

(Su(var)3–9). Originally identified in genetic screens for position effect variegation in Drosophila melanogaster and later shown to encode a histone H3 lysine 9 (H3K9) methylating enzyme.

Topologically associated domains

(TADs). Large genomic regions promoting regulatory interactions by forming higher-order chromatin structures separated by boundary regions.

Transgenerational inheritance

Transmission of epigenetic information that is passed on to gametes without alteration of the DNA sequence.

Trithorax

Originally identified in genetic screens for homeotic transformations in Drosophila melanogaster and later shown to encode a histone H3 lysine 4 (H3K4) methylating enzyme.

Writers

Enzymes that add histone modifications to chromatin.

X-chromosome inactivation

A process in which one of the two X chromosomes is randomly inactivated in female mammalian cells early in development.

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Allis, C., Jenuwein, T. The molecular hallmarks of epigenetic control. Nat Rev Genet 17, 487–500 (2016) doi:10.1038/nrg.2016.59

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