Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Histone post-translational modifications — cause and consequence of genome function

Nature Reviews Genetics volume 23, pages 563–580 (2022)Cite this article

Subjects

Abstract

Much has been learned since the early 1960s about histone post-translational modifications (PTMs) and how they affect DNA-templated processes at the molecular level. This understanding has been bolstered in the past decade by the identification of new types of histone PTM, the advent of new genome-wide mapping approaches and methods to deposit or remove PTMs in a locally and temporally controlled manner. Now, with the availability of vast amounts of data across various biological systems, the functional role of PTMs in important processes (such as transcription, recombination, replication, DNA repair and the modulation of genomic architecture) is slowly emerging. This Review explores the contribution of histone PTMs to the regulation of genome function by discussing when these modifications play a causative (or instructive) role in DNA-templated processes and when they are deposited as a consequence of such processes, to reinforce and record the event. Important advances in the field showing that histone PTMs can exert both direct and indirect effects on genome function are also presented.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Sites of selected histone post-translational modifications.
Fig. 2: Mechanisms that underlie the effects of histone post-translational modifications and recruitment of histone-modifying enzymes.
Fig. 3: Patterns of histone post-translational modifications during development.
Fig. 4: The coordination of genomic processes by histone post-translational modifications.

Similar content being viewed by others

References

  1. Luger, K., Dechassa, M. L. & Tremethick, D. J. New insights into nucleosome and chromatin structure: an ordered state or a disordered affair? Nat. Rev. Mol. Cell Biol. 13, 436–447 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lai, W. K. M. & Pugh, B. F. Understanding nucleosome dynamics and their links to gene expression and DNA replication. Nat. Rev. Mol. Cell Biol. 18, 548–562 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Turner, B. M. Decoding the nucleosome. Cell 75, 5–8 (1993). This review article introduces the concept of epigenetic code via histone PTMs.

    Article  CAS  PubMed  Google Scholar 

  4. Dai, Z., Ramesh, V. & Locasale, J. W. The evolving metabolic landscape of chromatin biology and epigenetics. Nat. Rev. Genet. 21, 737–753 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wiese, M. & Bannister, A. J. Two genomes, one cell: mitochondrial–nuclear coordination via epigenetic pathways. Mol. Metab. 38, 100942 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Martire, S. & Banaszynski, L. A. The roles of histone variants in fine-tuning chromatin organization and function. Nat. Rev. Mol. Cell Biol. 21, 522–541 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nacev, B. A. et al. The expanding landscape of ‘oncohistone’ mutations in human cancers. Nature 567, 473–478 (2019). This article highlights the prevalence of mutations in histone modification sites in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Byvoet, P., Shepherd, G. R., Hardin, J. M. & Noland, B. J. The distribution and turnover of labeled methyl groups in histone fractions of cultured mammalian cells. Arch. Biochem. Biophys. 148, 558–567 (1972).

    Article  CAS  PubMed  Google Scholar 

  9. Xhemalce B., Dawson M. A. & Bannister A. J. In Epigenetic Regulation and Epigenomics (ed. Meyers, R. A.) 657–703 (Wiley–Blackwell, 2012).

  10. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Cosgrove, M. S., Boeke, J. D. & Wolberger, C. Regulated nucleosome mobility and the histone code. Nat. Struct. Mol. Biol. 11, 1037–1043 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Neumann, H. et al. A method for genetically installing site-specific acetylation in recombinant histones defines the effects of H3 K56 acetylation. Mol. Cell 36, 153–163 (2009). Describes an elegant method for the production of recombinant histones with site-specific acetylations and reveals effects of H3K56ac on DNA breathing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. Durrin, L. K., Mann, R. K., Kayne, P. S. & Grunstein, M. Yeast histone H4 N-terminal sequence is required for promoter activation in vivo. Cell 65, 1023–1031 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Protacio, R. U., Li, G., Lowary, P. T. & Widom, J. Effects of histone tail domains on the rate of transcriptional elongation through a nucleosome. Mol. Cell Biol. 20, 8866–8878 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, W., Bone, J. R., Edmondson, D. G., Turner, B. M. & Roth, S. Y. Essential and redundant functions of histone acetylation revealed by mutation of target lysines and loss of the Gcn5p acetyltransferase. EMBO J. 17, 3155–3167 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nitsch, S., Zorro Shahidian, L. & Schneider, R. Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism. EMBO Rep. 22, e52774 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell 58, 203–215 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gowans, G. J. et al. Recognition of histone crotonylation by TAF14 links metabolic state to gene expression. Mol. Cell 76, 909–921.e903 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tidwell, T., Allfrey, V. G. & Mirsky, A. E. The methylation of histones during regeneration of the liver. J. Biol. Chem. 243, 707–715 (1968).

    Article  CAS  PubMed  Google Scholar 

  25. Bannister, A. J., Schneider, R. & Kouzarides, T. Histone methylation: dynamic or static? Cell 109, 801–806 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Henikoff, S. & Shilatifard, A. Histone modification: cause or cog? Trends Genet. 27, 389–396 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Talbert, P. B., Meers, M. P. & Henikoff, S. Old cogs, new tricks: the evolution of gene expression in a chromatin context. Nat. Rev. Genet. 20, 283–297 (2019).

    Article  CAS  PubMed  Google Scholar 

  28. Chen, K. et al. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes. Nat. Genet. 47, 1149–1157 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Benayoun, B. A. et al. H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell 158, 673–688 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131, 58–69 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Lauberth, S. M. et al. H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation. Cell 152, 1021–1036 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cano-Rodriguez, D. et al. Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner. Nat. Commun. 7, 12284 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Newman, J. R. et al. Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise. Nature 441, 840–846 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Dahl, J. A. et al. Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition. Nature 537, 548–552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang, B. et al. Allelic reprogramming of the histone modification H3K4me3 in early mammalian development. Nature 537, 553–557 (2016). The preceding two studies reveal the atypical distribution of H3K4me3 during early mammalian development.

    Article  CAS  PubMed  Google Scholar 

  36. Erkek, S. et al. Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa. Nat. Struct. Mol. Biol. 20, 868–875 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Ng, H. H., Robert, F., Young, R. A. & Struhl, K. Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Mol. Cell 11, 709–719 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Petruk, S. et al. Trithorax and dCBP acting in a complex to maintain expression of a homeotic gene. Science 294, 1331–1334 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Hormanseder, E. et al. H3K4 methylation-dependent memory of somatic cell identity inhibits reprogramming and development of nuclear transfer embryos. Cell Stem Cell 21, 135–143.e136 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Siklenka, K. et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, aab2006 (2015).

    Article  PubMed  CAS  Google Scholar 

  41. Lismer, A. et al. Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring. Dev. Cell 56, 671–686.e6 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931–21936 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dorighi, K. M. et al. Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation. Mol. Cell 66, 568–576.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rickels, R. et al. Histone H3K4 monomethylation catalyzed by TRR and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability. Nat. Genet. 49, 1647–1653 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang, T., Zhang, Z., Dong, Q., Xiong, J. & Zhu, B. Histone H3K27 acetylation is dispensable for enhancer activity in mouse embryonic stem cells. Genome Biol. 21, 45 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bleckwehl, T. et al. Enhancer-associated H3K4 methylation safeguards in vitro germline competence. Nat. Commun. 12, 5771 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hughes, A. L., Kelley, J. R. & Klose, R. J. Understanding the interplay between CpG island-associated gene promoters and H3K4 methylation. Biochim. Biophys. Acta Gene Regul. Mech. 1863, 194567 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hontelez, S. et al. Embryonic transcription is controlled by maternally defined chromatin state. Nat. Commun. 6, 10148 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Murphy, P. J., Wu, S. F., James, C. R., Wike, C. L. & Cairns, B. R. Placeholder nucleosomes underlie germline-to-embryo DNA methylation reprogramming. Cell 172, 993–1006.e13 (2018).

    Article  CAS  PubMed  Google Scholar 

  51. Liu, X. et al. Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos. Nature 537, 558–562 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Hanna, C. W. et al. MLL2 conveys transcription-independent H3K4 trimethylation in oocytes. Nat. Struct. Mol. Biol. 25, 73–82 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bannister, A. J. et al. Spatial distribution of di- and tri-methyl lysine 36 of histone H3 at active genes. J. Biol. Chem. 280, 17732–17736 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Vakoc, C. R., Sachdeva, M. M., Wang, H. X. & Blobel, G. A. Profile of histone lysine methylation across transcribed mammalian chromatin. Mol. Cell Biol. 26, 9185–9195 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kizer, K. O. et al. A novel domain in Set2 mediates RNA polymerase II interaction and couples histone H3K36 methylation with transcript elongation. Mol. Cell Biol. 25, 3305–3316 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Carrozza, M. J. et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123, 581–592 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Luco, R. F. et al. Regulation of alternative splicing by histone modifications. Science 327, 996–1000 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Huang, H. L. et al. Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally. Nature 567, 414–419 (2019). This article reveals cross-talk between RNA and histone modifications and thus bridges epitranscriptomics and epigenetics.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Meers, M. P. et al. Histone gene replacement reveals a post-transcriptional role for H3K36 in maintaining metazoan transcriptome fidelity. eLife 6, e23249 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Van Rechem, C. et al. Collective regulation of chromatin modifications predicts replication timing during cell cycle. Cell Rep. 37, 109799 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Weinberg, D. N. et al. The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape. Nature 573, 281–286 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dawson, M. A. et al. Three distinct patterns of histone H3Y41 phosphorylation mark active genes. Cell Rep. 2, 470–477 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Brehove, M. et al. Histone core phosphorylation regulates DNA accessibility. J. Biol. Chem. 290, 22612–22621 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lo, W. S. et al. Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol. Cell 5, 917–926 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Zippo, A. et al. Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. Cell 138, 1122–1136 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Hake, S. B. et al. Serine 31 phosphorylation of histone variant H3.3 is specific to regions bordering centromeres in metaphase chromosomes. Proc. Natl Acad. Sci. USA 102, 6344–6349 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Martire, S. et al. Phosphorylation of histone H3.3 at serine 31 promotes p300 activity and enhancer acetylation. Nat. Genet. 51, 941–946 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Armache, A. et al. Histone H3.3 phosphorylation amplifies stimulation-induced transcription. Nature 583, 852–857 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sitbon, D., Boyarchuk, E., Dingli, F., Loew, D. & Almouzni, G. Histone variant H3.3 residue S31 is essential for Xenopus gastrulation regardless of the deposition pathway. Nat. Commun. 11, 1256 (2020). The above three articles identify and demonstrate a functional role for modification of a histone variant-specific residue.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Macdonald, N. et al. Molecular basis for the recognition of phosphorylated and phosphoacetylated histone H3 by 14-3-3. Mol. Cell 20, 199–211 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Schneider, R., Bannister, A. J., Weise, C. & Kouzarides, T. Direct binding of INHAT to H3 tails disrupted by modifications. J. Biol. Chem. 279, 23859–23862 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Gehani, S. S. et al. Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation. Mol. Cell 39, 886–900 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Fischle, W. et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438, 1116–1122 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Schuettengruber, B. & Cavalli, G. Recruitment of polycomb group complexes and their role in the dynamic regulation of cell fate choice. Development 136, 3531–3542 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Simon, J. A. & Kingston, R. E. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat. Rev. Mol. Cell Biol. 10, 697–708 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Aranda, S., Mas, G. & Di Croce, L. Regulation of gene transcription by Polycomb proteins. Sci. Adv. 1, e1500737 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Pengelly, A. R., Copur, O., Jackle, H., Herzig, A. & Muller, J. A histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. Science 339, 698–699 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Pengelly, A. R., Kalb, R., Finkl, K. & Muller, J. Transcriptional repression by PRC1 in the absence of H2A monoubiquitylation. Genes Dev. 29, 1487–1492 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Blackledge, N. P. et al. PRC1 catalytic activity is central to Polycomb system function. Mol. Cell 77, 857–874.e9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tamburri, S. et al. Histone H2AK119 mono-ubiquitination is essential for Polycomb-mediated transcriptional repression. Mol. Cell 77, 840–856.e845 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 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 

  83. 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 

  84. Plys, A. J. et al. Phase separation of Polycomb-repressive complex 1 is governed by a charged disordered region of CBX2. Genes Dev. 33, 799–813 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Tatavosian, R. et al. Nuclear condensates of the Polycomb protein chromobox 2 (CBX2) assemble through phase separation. J. Biol. Chem. 294, 1451–1463 (2019).

    Article  CAS  PubMed  Google Scholar 

  86. Mei, H. et al. H2AK119ub1 guides maternal inheritance and zygotic deposition of H3K27me3 in mouse embryos. Nat. Genet. 53, 539–550 (2021).

    Article  CAS  PubMed  Google Scholar 

  87. Chen, Z., Djekidel, M. N. & Zhang, Y. Distinct dynamics and functions of H2AK119ub1 and H3K27me3 in mouse preimplantation embryos. Nat. Genet. 53, 551–563 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Inoue, A., Jiang, L., Lu, F., Suzuki, T. & Zhang, Y. Maternal H3K27me3 controls DNA methylation-independent imprinting. Nature 547, 419–424 (2017). This article demonstrates a role for H3K27me3 in non-canonical imprinting.

    Article  CAS  PubMed  Google Scholar 

  89. Zenk, F. et al. Germ line-inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition. Science 357, 212–216 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. Coleman, R. T. & Struhl, G. Causal role for inheritance of H3K27me3 in maintaining the OFF state of a Drosophila HOX gene. Science 356, eaai8236 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Escobar, T. M. et al. Active and repressed chromatin domains exhibit distinct nucleosome segregation during DNA replication. Cell 179, 953–963.e11 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Riising, E. M. et al. Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide. Mol. Cell 55, 347–360 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Allshire, R. C. & Madhani, H. D. Ten principles of heterochromatin formation and function. Nat. Rev. Mol. Cell Biol. 19, 229–244 (2018).

    Article  CAS  PubMed  Google Scholar 

  94. Nicetto, D. & Zaret, K. S. Role of H3K9me3 heterochromatin in cell identity establishment and maintenance. Curr. Opin. Genet. Dev. 55, 1–10 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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 

  96. 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 

  97. Canzio, D. et al. Chromodomain-mediated oligomerization of HP1 suggests a nucleosome-bridging mechanism for heterochromatin assembly. Mol. Cell 41, 67–81 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Jack, A. P. et al. H3K56me3 is a novel, conserved heterochromatic mark that largely but not completely overlaps with H3K9me3 in both regulation and localization. PLoS One 8, e51765 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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 

  100. Daujat, S. et al. H3K64 trimethylation marks heterochromatin and is dynamically remodeled during developmental reprogramming. Nat. Struct. Mol. Biol. 16, 777–781 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ninova, M., Fejes Toth, K. & Aravin, A. A. The control of gene expression and cell identity by H3K9 trimethylation. Development 146, dev181180 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nicetto, D. et al. H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification. Science 363, 294–297 (2019). This article demonstrates a function for H3K9me3 in regulating tissue-specific gene expression in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. McCarthy, R. L. et al. Diverse heterochromatin-associated proteins repress distinct classes of genes and repetitive elements. Nat. Cell Biol. 23, 905–914 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Burton, A. et al. Heterochromatin establishment during early mammalian development is regulated by pericentromeric RNA and characterized by non-repressive H3K9me3. Nat. Cell Biol. 22, 767–778 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019). This article reveals the widespread occurrence of a new histone PTM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Farrelly, L. A. et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 567, 535–539 (2019). This study uncovers monoaminylation as a new class of histone PTM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lepack, A. E. et al. Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking. Science 368, 197–201 (2020). This work demonstrates a physiological role for a new type of histone monoaminylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gehre, M. et al. Lysine 4 of histone H3.3 is required for embryonic stem cell differentiation, histone enrichment at regulatory regions and transcription accuracy. Nat. Genet. 52, 273–282 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  111. Shimko, J. C., North, J. A., Bruns, A. N., Poirier, M. G. & Ottesen, J. J. Preparation of fully synthetic histone H3 reveals that acetyl-lysine 56 facilitates protein binding within nucleosomes. J. Mol. Biol. 408, 187–204 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. North, J. A. et al. Regulation of the nucleosome unwrapping rate controls DNA accessibility. Nucleic Acids Res. 40, 10215–10227 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Di Cerbo, V. et al. Acetylation of histone H3 at lysine 64 regulates nucleosome dynamics and facilitates transcription. eLife 3, e01632 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Lange, U. C. et al. Dissecting the role of H3K64me3 in mouse pericentromeric heterochromatin. Nat. Commun. 4, 2233 (2013).

    Article  PubMed  CAS  Google Scholar 

  115. North, J. A. et al. Phosphorylation of histone H3(T118) alters nucleosome dynamics and remodeling. Nucleic Acids Res. 39, 6465–6474 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tropberger, P. et al. Regulation of transcription through acetylation of H3K122 on the lateral surface of the histone octamer. Cell 152, 859–872 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Zorro Shahidian, L. et al. Succinylation of H3K122 destabilizes nucleosomes and enhances transcription. EMBO Rep. 22, e51009 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bao, X. et al. Glutarylation of histone H4 lysine 91 regulates chromatin dynamics. Mol. Cell 76, 660–675.e9 (2019).

    Article  CAS  PubMed  Google Scholar 

  119. Tessarz, P. et al. Glutamine methylation in histone H2A is an RNA-polymerase-I-dedicated modification. Nature 505, 564–568 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Mawer, J. S. P. et al. Nhp2 is a reader of H2AQ105me and part of a network integrating metabolism with rRNA synthesis. EMBO Rep. 22, e52435 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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).

    Article  PubMed  Google Scholar 

  122. Lawrence, M., Daujat, S. & Schneider, R. Lateral thinking: how histone modifications regulate gene expression. Trends Genet. 32, 42–56 (2016).

    Article  CAS  PubMed  Google Scholar 

  123. Schubeler, D. et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 18, 1263–1271 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Godfrey, L. et al. DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation. Nat. Commun. 10, 2803 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Spruce, C. et al. HELLS and PRDM9 form a pioneer complex to open chromatin at meiotic recombination hot spots. Genes Dev. 34, 398–412 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Mihola, O. et al. Rat PRDM9 shapes recombination landscapes, duration of meiosis, gametogenesis, and age of fertility. BMC Biol. 19, 86 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kaiser, V. B. & Semple, C. A. Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline. Genome Biol. 19, 101 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Grey, C. et al. In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites. Genome Res. 27, 580–590 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Liu, C., Zhang, Y., Liu, C. C. & Schatz, D. G. Structural insights into the evolution of the RAG recombinase. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00628-6 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

    Article  CAS  PubMed  Google Scholar 

  133. Clouaire, T. & Legube, G. A snapshot on the cis chromatin response to DNA double-strand breaks. Trends Genet. 35, 330–345 (2019).

    Article  CAS  PubMed  Google Scholar 

  134. Arnould, C. et al. Loop extrusion as a mechanism for formation of DNA damage repair foci. Nature 590, 660–665 (2021). This study demonstrates a dependence of γH2A.X-containing repair foci on loop extrusion and genome topology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Thorslund, T. et al. Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. Nature 527, 389–393 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Mattiroli, F. et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell 150, 1182–1195 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Pesavento, J. J., Yang, H., Kelleher, N. L. & Mizzen, C. A. Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle. Mol. Cell Biol. 28, 468–486 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Botuyan, M. V. et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361–1373 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Fradet-Turcotte, A. et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499, 50–54 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Nakamura, K. et al. H4K20me0 recognition by BRCA1–BARD1 directs homologous recombination to sister chromatids. Nat. Cell Biol. 21, 311–318 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Becker, J. R. et al. BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination. Nature 596, 433–437 (2021).

    Article  CAS  PubMed  Google Scholar 

  142. Pfister, S. X. et al. SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep. 7, 2006–2018 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Gong, F., Clouaire, T., Aguirrebengoa, M., Legube, G. & Miller, K. M. Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair. J. Cell Biol. 216, 1959–1974 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Li, X. et al. Histone demethylase KDM5B is a key regulator of genome stability. Proc. Natl Acad. Sci. USA 111, 7096–7101 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Ayrapetov, M. K., Gursoy-Yuzugullu, O., Xu, C., Xu, Y. & Price, B. D. DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin. Proc. Natl Acad. Sci. USA 111, 9169–9174 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Alagoz, M. et al. SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells. Nucleic Acids Res. 43, 7931–7944 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Qin, B. et al. UFL1 promotes histone H4 ufmylation and ATM activation. Nat. Commun. 10, 1242 (2019). This study demonstrates a role for a new histone PTM in DNA repair.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Miotto, B. & Struhl, K. HBO1 histone acetylase activity is essential for DNA replication licensing and inhibited by Geminin. Mol. Cell 37, 57–66 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Sansam, C. G. et al. A mechanism for epigenetic control of DNA replication. Genes Dev. 32, 224–229 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Kuo, A. J. et al. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier–Gorlin syndrome. Nature 484, 115–119 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Beck, D. B. et al. The role of PR-Set7 in replication licensing depends on Suv4-20h. Genes Dev. 26, 2580–2589 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Tardat, M. et al. The histone H4 Lys 20 methyltransferase PR-Set7 regulates replication origins in mammalian cells. Nat. Cell Biol. 12, 1086–1093 (2010).

    Article  CAS  PubMed  Google Scholar 

  153. Lim, H. J. et al. The G2/M regulator histone demethylase PHF8 is targeted for degradation by the anaphase-promoting complex containing CDC20. Mol. Cell Biol. 33, 4166–4180 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Long, H. et al. H2A.Z facilitates licensing and activation of early replication origins. Nature 577, 576–581 (2020).

    Article  CAS  PubMed  Google Scholar 

  155. Rondinelli, B. et al. H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing. Nucleic Acids Res. 43, 2560–2574 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wu, R., Wang, Z., Zhang, H., Gan, H. & Zhang, Z. H3K9me3 demethylase Kdm4d facilitates the formation of pre-initiative complex and regulates DNA replication. Nucleic Acids Res. 45, 169–180 (2017).

    Article  CAS  PubMed  Google Scholar 

  157. Mishra, S. et al. Cross-talk between lysine-modifying enzymes controls site-specific DNA amplifications. Cell 175, 1716 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Black, J. C. et al. KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell 154, 541–555 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Klein, K. N. et al. Replication timing maintains the global epigenetic state in human cells. Science 372, 371–378 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Pope, B. D. et al. Topologically associating domains are stable units of replication-timing regulation. Nature 515, 402–405 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Rowley, M. J. & Corces, V. G. Organizational principles of 3D genome architecture. Nat. Rev. Genet. 19, 789–800 (2018).

    Article  CAS  PubMed  Google Scholar 

  162. Falk, M. et al. Heterochromatin drives compartmentalization of inverted and conventional nuclei. Nature 570, 395–399 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Feng, Y. et al. Simultaneous epigenetic perturbation and genome imaging reveal distinct roles of H3K9me3 in chromatin architecture and transcription. Genome Biol. 21, 296 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Bian, Q., Anderson, E. C., Yang, Q. & Meyer, B. J. Histone H3K9 methylation promotes formation of genome compartments in Caenorhabditis elegans via chromosome compaction and perinuclear anchoring. Proc. Natl Acad. Sci. USA 117, 11459–11470 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Montavon, T. et al. Complete loss of H3K9 methylation dissolves mouse heterochromatin organization. Nat. Commun. 12, 4359 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. van Steensel, B. & Belmont, A. S. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 169, 780–791 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Towbin, B. D. et al. Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. Cell 150, 934–947 (2012).

    Article  CAS  PubMed  Google Scholar 

  168. Kind, J. et al. Single-cell dynamics of genome-nuclear lamina interactions. Cell 153, 178–192 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Poleshko, A. et al. H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis. eLife 8, e49278 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Boettiger, A. N. et al. Super-resolution imaging reveals distinct chromatin folding for different epigenetic states. Nature 529, 418–422 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kundu, S. et al. Polycomb repressive complex 1 generates discrete compacted domains that change during differentiation. Mol. Cell 65, 432–446.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Du, Z. et al. Polycomb group proteins regulate chromatin architecture in mouse oocytes and early embryos. Mol. Cell 77, 825–839.e7 (2020).

    Article  CAS  PubMed  Google Scholar 

  173. Rhodes, J. D. P. et al. Cohesin disrupts polycomb-dependent chromosome interactions in embryonic stem cells. Cell Rep. 30, 820–835.e10 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Mas, G. et al. Promoter bivalency favors an open chromatin architecture in embryonic stem cells. Nat. Genet. 50, 1452–1462 (2018).

    Article  CAS  PubMed  Google Scholar 

  175. Huang, Y. et al. Polycomb-dependent differential chromatin compartmentalization determines gene coregulation in Arabidopsis. Genome Res. 31, 1230–1244 (2021).

    Article  PubMed Central  Google Scholar 

  176. Crane, E. et al. Condensin-driven remodelling of X chromosome topology during dosage compensation. Nature 523, 240–244 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Anderson, E. C. et al. X chromosome domain architecture regulates Caenorhabditis elegans lifespan but not dosage compensation. Dev. Cell 51, 192–207.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Brejc, K. et al. Dynamic control of X chromosome conformation and repression by a histone H4K20 demethylase. Cell 171, 85–102.e23 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Flavahan, W. A. et al. Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs. Nature 575, 229–233 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Faulkner, S., Maksimovic, I. & David, Y. A chemical field guide to histone nonenzymatic modifications. Curr. Opin. Chem. Biol. 63, 180–187 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  182. Hebbes, T. R., Thorne, A. W. & Crane-Robinson, C. A direct link between core histone acetylation and transcriptionally active chromatin. EMBO J. 7, 1395–1402 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Brind’Amour, J. et al. An ultra-low-input native ChIP-seq protocol for genome-wide profiling of rare cell populations. Nat. Commun. 6, 6033 (2015).

    Article  PubMed  CAS  Google Scholar 

  184. Skene, P. J. & Henikoff, S. An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. eLife 6, e21856 (2017). Describes mapping of protein–DNA interactions by CUT&RUN as an attractive alternative to ChIP–seq.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Hainer, S. J. & Fazzio, T. G. High-resolution chromatin profiling using CUT&RUN. Curr. Protoc. Mol. Biol. 126, e85 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Brahma, S. & Henikoff, S. RSC-associated subnucleosomes define MNase-sensitive promoters in yeast. Mol. Cell 73, 238–249.e3 (2019).

    Article  CAS  PubMed  Google Scholar 

  187. Kaya-Okur, H. S. et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat. Commun. 10, 1930 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Meers, M. P., Janssens, D. H. & Henikoff, S. Multifactorial chromatin regulatory landscapes at single cell resolution. Preprint at bioRxiv https://doi.org/10.1101/2021.07.08.451691v1.full (2021).

    Article  Google Scholar 

  189. Gopalan, S., Wang, Y., Harper, N. W., Garber, M. & Fazzio, T. G. Simultaneous profiling of multiple chromatin proteins in the same cells. Mol. Cell 81, 4736–4746.e5 (2021).

    Article  CAS  PubMed  Google Scholar 

  190. Deng, Y. et al. Spatial-CUT&Tag: spatially resolved chromatin modification profiling at the cellular level. Science 375, 681–686 (2022).

    Article  CAS  PubMed  Google Scholar 

  191. Harada, A. et al. A chromatin integration labelling method enables epigenomic profiling with lower input. Nat. Cell Biol. 21, 287–296 (2019).

    Article  CAS  PubMed  Google Scholar 

  192. Altemose, N. et al. DiMeLo-seq: a long-read, single-molecule method for mapping protein-DNA interactions genome-wide. Preprint at bioRxiv https://doi.org/10.1101/2021.07.06.451383v1 (2021).

    Article  Google Scholar 

  193. Armeev, G. A., Kniazeva, A. S., Komarova, G. A., Kirpichnikov, M. P. & Shaytan, A. K. Histone dynamics mediate DNA unwrapping and sliding in nucleosomes. Nat. Commun. 12, 2387 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Xia, W. et al. Resetting histone modifications during human parental-to-zygotic transition. Science 365, 353–360 (2019).

    Article  CAS  PubMed  Google Scholar 

  195. van de Werken, C. et al. Paternal heterochromatin formation in human embryos is H3K9/HP1 directed and primed by sperm-derived histone modifications. Nat. Commun. 5, 5868 (2014).

    Article  PubMed  CAS  Google Scholar 

  196. Wang, C. et al. Reprogramming of H3K9me3-dependent heterochromatin during mammalian embryo development. Nat. Cell Biol. 20, 620–631 (2018).

    Article  CAS  PubMed  Google Scholar 

  197. Boskovic, A. et al. Analysis of active chromatin modifications in early mammalian embryos reveals uncoupling of H2A.Z acetylation and H3K36 trimethylation from embryonic genome activation. Epigenetics 7, 747–757 (2012).

    Article  CAS  PubMed  Google Scholar 

  198. Zheng, H. et al. Resetting epigenetic memory by reprogramming of histone modifications in mammals. Mol. Cell 63, 1066–1079 (2016).

    Article  CAS  PubMed  Google Scholar 

  199. Lindeman, L. C. et al. Prepatterning of developmental gene expression by modified histones before zygotic genome activation. Dev. Cell 21, 993–1004 (2011).

    Article  CAS  PubMed  Google Scholar 

  200. Vastenhouw, N. L. et al. Chromatin signature of embryonic pluripotency is established during genome activation. Nature 464, 922–926 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Laue, K., Rajshekar, S., Courtney, A. J., Lewis, Z. A. & Goll, M. G. The maternal to zygotic transition regulates genome-wide heterochromatin establishment in the zebrafish embryo. Nat. Commun. 10, 1551 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Zhang, B. et al. Widespread enhancer dememorization and promoter priming during parental-to-zygotic transition. Mol. Cell 72, 673–686.e6 (2018).

    Article  PubMed  CAS  Google Scholar 

  203. Akkers, R. C. et al. A hierarchy of H3K4me3 and H3K27me3 acquisition in spatial gene regulation in Xenopus embryos. Dev. Cell 17, 425–434 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Oikawa, M. et al. Epigenetic homogeneity in histone methylation underlies sperm programming for embryonic transcription. Nat. Commun. 11, 3491 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Chen, K. et al. A global change in RNA polymerase II pausing during the Drosophila midblastula transition. eLife 2, e00861 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Li, X. Y., Harrison, M. M., Villalta, J. E., Kaplan, T. & Eisen, M. B. Establishment of regions of genomic activity during the Drosophila maternal to zygotic transition. eLife 3, e03737 (2014).

    Article  PubMed Central  CAS  Google Scholar 

  207. Seller, C. A., Cho, C. Y. & O’Farrell, P. H. Rapid embryonic cell cycles defer the establishment of heterochromatin by Eggless/SetDB1 in Drosophila. Genes Dev. 33, 403–417 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Mutlu, B. et al. Regulated nuclear accumulation of a histone methyltransferase times the onset of heterochromatin formation in C. elegans embryos. Sci. Adv. 4, eaat6224 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Wang, S., Fisher, K. & Poulin, G. B. Lineage specific trimethylation of H3 on lysine 4 during C. elegans early embryogenesis. Dev. Biol. 355, 227–238 (2011).

    Article  CAS  PubMed  Google Scholar 

  210. Kaneshiro, K. R., Rechtsteiner, A. & Strome, S. Sperm-inherited H3K27me3 impacts offspring transcription and development in C. elegans. Nat. Commun. 10, 1271 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Kreher, J. et al. Distinct roles of two histone methyltransferases in transmitting H3K36me3-based epigenetic memory across generations in Caenorhabditis elegans. Genetics 210, 969–982 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Methot, S. P. et al. H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity. Nat. Cell Biol. 23, 1163–1175 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Bhattacharyya, T. et al. Prdm9 and meiotic cohesin proteins cooperatively promote DNA double-strand break formation in mammalian spermatocytes. Curr. Biol. 31, 1351 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Gibson, B. A. et al. Organization of chromatin by intrinsic and regulated phase separation. Cell 179, 470–484.e21 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Sabari, B. R. et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361, eaar3958 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. Cho, W. K. et al. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates. Science 361, 412–415 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Chong, S. et al. Imaging dynamic and selective low-complexity domain interactions that control gene transcription. Science 361, eaar2555 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Strickfaden, H. et al. Condensed chromatin behaves like a solid on the mesoscale in vitro and in living cells. Cell 183, 1772–1784.e13 (2020).

    Article  CAS  PubMed  Google Scholar 

  219. Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Wang, L. et al. Histone modifications regulate chromatin compartmentalization by contributing to a phase separation mechanism. Mol. Cell 76, 646–659.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  222. Erdel, F. et al. Mouse heterochromatin adopts digital compaction states without showing hallmarks of HP1-driven liquid-liquid phase separation. Mol. Cell 78, 236–249.e7 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. McSwiggen, D. T., Mir, M., Darzacq, X. & Tjian, R. Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences. Genes Dev. 33, 1619–1634 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Gallego, L. D. et al. Phase separation directs ubiquitination of gene-body nucleosomes. Nature 579, 592–597 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Eeftens, J. M., Kapoor, M., Michieletto, D. & Brangwynne, C. P. Polycomb condensates can promote epigenetic marks but are not required for sustained chromatin compaction. Nat. Commun. 12, 5888 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Snowden, A. W., Gregory, P. D., Case, C. C. & Pabo, C. O. Gene-specific targeting of H3K9 methylation is sufficient for initiating repression in vivo. Curr. Biol. 12, 2159–2166 (2002).

    Article  CAS  PubMed  Google Scholar 

  227. Gaj, T., Gersbach, C. A. & Barbas, C. F. 3rd ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 31, 397–405 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Martinez-Balbas, M. A. et al. The acetyltransferase activity of CBP stimulates transcription. EMBO J. 17, 2886–2893 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Chiarella, A. M. et al. Dose-dependent activation of gene expression is achieved using CRISPR and small molecules that recruit endogenous chromatin machinery. Nat. Biotechnol. 38, 50–55 (2020).

    Article  CAS  PubMed  Google Scholar 

  230. Kearns, N. A. et al. Functional annotation of native enhancers with a Cas9–histone demethylase fusion. Nat. Methods 12, 401–403 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Hilton, I. B. et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat. Biotechnol. 33, 510–517 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Kwon, D. Y., Zhao, Y. T., Lamonica, J. M. & Zhou, Z. Locus-specific histone deacetylation using a synthetic CRISPR-Cas9-based HDAC. Nat. Commun. 8, 15315 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. O’Geen, H. et al. dCas9-based epigenome editing suggests acquisition of histone methylation is not sufficient for target gene repression. Nucleic Acids Res. 45, 9901–9916 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  234. Verkuijl, S. A. & Rots, M. G. The influence of eukaryotic chromatin state on CRISPR–Cas9 editing efficiencies. Curr. Opin. Biotechnol. 55, 68–73 (2019).

    Article  CAS  PubMed  Google Scholar 

  235. Jain, S. et al. TALEN outperforms Cas9 in editing heterochromatin target sites. Nat. Commun. 12, 606 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The R.S. laboratory is supported by the German Research Foundation (DFG) through SFB 1064 (Project-ID 213249687) and SFB 1309 (Project-ID 325871075), as well as the Helmholtz Gesellschaft. A.J.B is supported by grants from Cancer Research UK (RG96894 and C6946/A24843) and the Wellcome Trust (WT203144). G.M.-Z. is supported by a Juan de la Cierva postdoctoral contract (IJC2019-039988) from the Spanish Ministry of Science and Innovation and a fellowship from “la Caixa” Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No. 847648. The fellowship code is LCF/BQ/PR21/11840007. A.B. is supported by the DFG through SFB 1064 (Project-ID 213249687) as well as the Helmholtz Gesellschaft. The authors apologize to colleagues whose important studies they were unable to cite owing to space constraints.

Author information

Author notes

  1. These authors contributed equally: Gonzalo Millán-Zambrano, Adam Burton.

Authors and Affiliations

  1. Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain

    Gonzalo Millán-Zambrano

  2. Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Seville, Spain

    Gonzalo Millán-Zambrano

  3. Institute of Epigenetics and Stem Cells, Helmholtz Center Munich, Munich, Germany

    Adam Burton

  4. Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK

    Andrew J. Bannister

  5. Institute of Functional Epigenetics, Helmholtz Center Munich, Munich, Germany

    Robert Schneider

  6. Faculty of Biology, Ludwig Maximilian University (LMU) of Munich, Munich, Germany

    Robert Schneider

Authors
  1. Gonzalo Millán-Zambrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam Burton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew J. Bannister
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to discussions of the article content, writing the paper, and to review and/or editing of the manuscript before submission.

Corresponding authors

Correspondence to Andrew J. Bannister or Robert Schneider.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Genetics thanks J. Workman, S. Sidoli and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Euchromatin

Non-condensed chromatin state that is enriched in genes and permissive for transcription.

Topologically associating domains

(TADs). Insulated 3D chromosomal domains of sub-megabase size, within which DNA sequences preferentially contact each other.

Super-enhancers

Expanded enhancer sequences that cluster in the same genomic region and display very high levels of histone 3 lysine 27 acetylation (H3K27ac) and H3K4 monomethylation (H3K4me1), bind to bromodomain-containing protein 4 (BRD4) and transcription factors and produce high amounts of short enhancer RNAs.

Epigenetic events

Heritable phenotypic changes that are independent of changes to the DNA sequence.

Chromodomain

A conserved structural domain of ~40–50 amino acids that is commonly found in proteins associated with chromatin remodelling and with proteins that bind to methylated lysine residues in histones.

Transcriptional consistency

The uniformity of gene expression in a cell population, defined as a low variance in expression when scaled to the average level of expression.

Transcriptionally quiescent

Describes a cellular state in which very low to no active gene expression is observed, for example, in fully differentiated gametes.

Zygotic genome activation

The stage of development, which can vary widely between species, at which expression of the embryonic genome is strongly activated and thus control of development transfers from the maternal to the embryonic contribution.

Constitutive heterochromatin

A permanently condensed chromatin conformation that is repressive for transcription and is commonly found at repetitive regions of the genome, such as centromeres and telomeres.

Facultative heterochromatin

Reversibly condensed chromatin conformation that is transcriptionally silent.

Liquid–liquid phase separation

The process by which a liquid demixes into distinct phases with differing solute concentrations; this process is thought to drive the formation of various membraneless organelles and condensates in cells.

Centromere

Repetitive region of the chromosome that attaches to the mitotic spindle and is responsible for ensuring accurate transmission of the genome during cell division.

Telomere

Repetitive region at ends of a chromosome that protects chromosome termini from progressive degradation.

Histone octamer lateral surface

The positively charged outer surface of the histone octamer around which DNA is wrapped.

V(D)J recombination

A site-specific recombination event that enables a wide variety of immunoglobulins to be assembled for expression.

Homologous recombination

A template-based mechanism for accurate repair of double-stranded breaks in DNA.

Non-homologous end-joining

(NHEJ). An error-prone mechanism for repairing double-stranded breaks in DNA involving the ligation of two free DNA ends.

Bromodomain

A conserved structural domain of ~40–50 amino acids that is commonly found in proteins associated with chromatin remodelling and with proteins that bind to acetylated lysine residues in histones.

Insulator

A genomic element that acts as a barrier, preventing interactions between contiguous regions of the genome.

Chromatin loop extrusion

A motor-driven process in which a loop-extruding factor translocates along the chromatin fibre in opposite directions, thereby growing a chromatin loop.

Chromosome conformation capture

Methods of analysing genome organization based on the detection of interactions between genomic loci that are physically close together but might be widely separated in the nucleotide sequence; a strong signal indicates an increased frequency of such interactions.

Lamina-associated domains

Megabase-scale regions of the genome that interact with the nuclear lamina, are gene-poor, late-replicating and that correspond to heterochromatin and the B compartment.

Polycomb-associating domains

(PADs). Self-associating compartment-like structures marked by histone 3 lysine 27 trimethylation (H3K27me3).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Millán-Zambrano, G., Burton, A., Bannister, A.J. et al. Histone post-translational modifications — cause and consequence of genome function. Nat Rev Genet 23, 563–580 (2022). https://doi.org/10.1038/s41576-022-00468-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-022-00468-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing