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:

The molecular principles of gene regulation by Polycomb repressive complexes

Abstract

Precise control of gene expression is fundamental to cell function and development. Although ultimately gene expression relies on DNA-binding transcription factors to guide the activity of the transcription machinery to genes, it has also become clear that chromatin and histone post-translational modification have fundamental roles in gene regulation. Polycomb repressive complexes represent a paradigm of chromatin-based gene regulation in animals. The Polycomb repressive system comprises two central protein complexes, Polycomb repressive complex 1 (PRC1) and PRC2, which are essential for normal gene regulation and development. Our early understanding of Polycomb function relied on studies in simple model organisms, but more recently it has become apparent that this system has expanded and diverged in mammals. Detailed studies are now uncovering the molecular mechanisms that enable mammalian PRC1 and PRC2 to identify their target sites in the genome, communicate through feedback mechanisms to create Polycomb chromatin domains and control transcription to regulate gene expression. In this Review, we discuss and contextualize the emerging principles that define how this fascinating chromatin-based system regulates gene expression in mammals.

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

Access options

Buy this article

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

Fig. 1: A diverse repertoire of mammalian Polycomb repressive complexes.
Fig. 2: Primary mechanisms of Polycomb target site identification.
Fig. 3: Formation and spreading of Polycomb chromatin domains.
Fig. 4: Polycomb bodies, long-range interactions and phase separation.
Fig. 5: Models of Polycomb chromatin domain formation and gene regulation.
Fig. 6: Mechanisms of Polycomb-mediated gene regulation.
Fig. 7: CpG islands and chromatin bistability.

Similar content being viewed by others

References

  1. Haberle, V. & Stark, A. Eukaryotic core promoters and the functional basis of transcription initiation. Nat. Rev. Mol. Cell Biol. 19, 621–637 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Kassis, J. A., Kennison, J. A. & Tamkun, J. W. Polycomb and Trithorax group genes in Drosophila. Genetics 206, 1699–1725 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Schuettengruber, B., Bourbon, H. M., Di Croce, L. & Cavalli, G. Genome regulation by Polycomb and Trithorax: 70 years and counting. Cell 171, 34–57 (2017).

    CAS  PubMed  Google Scholar 

  4. de Napoles, M. et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell 7, 663–676 (2004).

    PubMed  Google Scholar 

  5. Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. 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).

    CAS  PubMed  Google Scholar 

  8. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123–1136 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Fursova, N. A. et al. Synergy between variant PRC1 complexes defines polycomb-mediated gene repression. Mol. Cell 74, 1020–1036 e1028 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Tolhuis, B. et al. Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nat. Genet. 38, 694–699 (2006).

    CAS  PubMed  Google Scholar 

  14. Schwartz, Y. B. et al. Genome-wide analysis of polycomb targets in Drosophila melanogaster. Nat. Genet. 38, 700–705 (2006).

    CAS  PubMed  Google Scholar 

  15. Piunti, A. & Shilatifard, A. The roles of Polycomb repressive complexes in mammalian development and cancer. Nat. Rev. Mol. Cell Biol. 22, 326–345 (2021).

    CAS  PubMed  Google Scholar 

  16. Deevy, O. & Bracken, A. P. PRC2 functions in development and congenital disorders. Development 146, dev181354 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Laugesen, A., Hojfeldt, J. W. & Helin, K. Molecular mechanisms directing PRC2 recruitment and H3K27 methylation. Mol. Cell 74, 8–18 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cohen, I., Bar, C. & Ezhkova, E. Activity of PRC1 and histone H2AK119 monoubiquitination: revising popular misconceptions. Bioessays 42, e1900192 (2020).

    PubMed  PubMed Central  Google Scholar 

  19. Gao, Z. et al. PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes. Mol. Cell 45, 344–356 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Li, Z. et al. Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex. J. Biol. Chem. 281, 20643–20649 (2006).

    CAS  PubMed  Google Scholar 

  21. Buchwald, G. et al. Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins Bmi1 and Ring1b. EMBO J. 25, 2465–2474 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Bentley, M. L. et al. Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex. EMBO J. 30, 3285–3297 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Hauri, S. et al. A high-density map for navigating the human polycomb complexome. Cell Rep. 17, 583–595 (2016).

    CAS  PubMed  Google Scholar 

  24. Wang, R. et al. Polycomb group targeting through different binding partners of RING1B C-terminal domain. Structure 18, 966–975 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Levine, S. S. et al. The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans. Mol. Cell Biol. 22, 6070–6078 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Shao, Z. et al. Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 98, 37–46 (1999).

    CAS  PubMed  Google Scholar 

  27. Tavares, L. et al. RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell 148, 664–678 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. McGinty, R. K., Henrici, R. C. & Tan, S. Crystal structure of the PRC1 ubiquitylation module bound to the nucleosome. Nature 514, 591–596 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kalashnikova, A. A., Porter-Goff, M. E., Muthurajan, U. M., Luger, K. & Hansen, J. C. The role of the nucleosome acidic patch in modulating higher order chromatin structure. J. R. Soc. Interface 10, 20121022 (2013).

    PubMed  PubMed Central  Google Scholar 

  30. Rose, N. R. et al. RYBP stimulates PRC1 to shape chromatin-based communication between Polycomb repressive complexes. eLife 5, e.18591 (2016).

    Google Scholar 

  31. Taherbhoy, A. M., Huang, O. W. & Cochran, A. G. BMI1-RING1B is an autoinhibited RING E3 ubiquitin ligase. Nat. Commun. 6, 7621 (2015).

    PubMed  Google Scholar 

  32. Zhao, J. et al. RYBP/YAF2-PRC1 complexes and histone H1-dependent chromatin compaction mediate propagation of H2AK119ub1 during cell division. Nat. Cell Biol. 22, 439–452 (2020).

    CAS  PubMed  Google Scholar 

  33. Margueron, R. et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol. Cell 32, 503–518 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ciferri, C. et al. Molecular architecture of human polycomb repressive complex 2. eLife 1, e00005 (2012).

    PubMed  PubMed Central  Google Scholar 

  35. Kasinath, V. et al. Structures of human PRC2 with its cofactors AEBP2 and JARID2. Science 359, 940–944 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Glancy, E., Ciferri, C. & Bracken, A. P. Structural basis for PRC2 engagement with chromatin. Curr. Opin. Struct. Biol. 67, 135–144 (2020).

    PubMed  Google Scholar 

  37. Brooun, A. et al. Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance. Nat. Commun. 7, 11384 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Cao, R. & Zhang, Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol. Cell 15, 57–67 (2004).

    CAS  PubMed  Google Scholar 

  39. Jiao, L. & Liu, X. Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2. Science 350, aac4383 (2015).

    PubMed  PubMed Central  Google Scholar 

  40. Antonysamy, S. et al. Structural context of disease-associated mutations and putative mechanism of autoinhibition revealed by X-ray crystallographic analysis of the EZH2-SET domain. PLoS ONE 8, e84147 (2013).

    PubMed  PubMed Central  Google Scholar 

  41. Justin, N. et al. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. Nat. Commun. 7, 11316 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Finogenova, K. et al. Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3. eLife 9, e.61964 (2020).

    Google Scholar 

  43. Poepsel, S., Kasinath, V. & Nogales, E. Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes. Nat. Struct. Mol. Biol. 25, 154–162 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen, S., Jiao, L., Shubbar, M., Yang, X. & Liu, X. Unique structural platforms of Suz12 dictate distinct classes of PRC2 for chromatin binding. Mol. Cell 69, 840–852 e845 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Beringer, M. et al. EPOP functionally links elongin and polycomb in pluripotent stem cells. Mol. Cell 64, 645–658 (2016).

    CAS  PubMed  Google Scholar 

  46. Liefke, R., Karwacki-Neisius, V. & Shi, Y. EPOP interacts with elongin BC and USP7 to modulate the chromatin landscape. Mol. Cell 64, 659–672 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhang, Z. et al. PRC2 complexes with JARID2, MTF2, and esPRC2p48 in ES cells to modulate ES cell pluripotency and somatic cell reprogramming. Stem Cell 29, 229–240 (2011).

    Google Scholar 

  48. Sanulli, S. et al. Jarid2 methylation via the PRC2 complex regulates H3K27me3 deposition during cell differentiation. Mol. Cell 57, 769–783 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lee, C. H. et al. Distinct stimulatory mechanisms regulate the catalytic activity of polycomb repressive complex 2. Mol. Cell 70, 435–448 e435 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Conway, E. et al. A family of vertebrate-specific polycombs encoded by the LCOR/LCORL genes balance PRC2 subtype activities. Mol. Cell 70, 408–421 e408 (2018).

    CAS  PubMed  Google Scholar 

  51. Pajtler, K. W. et al. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol. 136, 211–226 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Piunti, A. et al. CATACOMB: an endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism. Sci. Adv. 5, eaax2887 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ragazzini, R. et al. EZHIP constrains polycomb repressive complex 2 activity in germ cells. Nat. Commun. 10, 3858 (2019).

    PubMed  PubMed Central  Google Scholar 

  54. Jain, S. U. et al. PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat. Commun. 10, 2146 (2019).

    PubMed  PubMed Central  Google Scholar 

  55. Cai, Y. et al. H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions. Nat. Commun. 12, 719 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Mendenhall, E. M. et al. GC-rich sequence elements recruit PRC2 in mammalian ES cells. PLoS Genet. 6, e1001244 (2010).

    PubMed  PubMed Central  Google Scholar 

  57. Ngan, C. Y. et al. Chromatin interaction analyses elucidate the roles of PRC2-bound silencers in mouse development. Nat. Genet. 52, 264–272 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Loubiere, V., Papadopoulos, G. L., Szabo, Q., Martinez, A. M. & Cavalli, G. Widespread activation of developmental gene expression characterized by PRC1-dependent chromatin looping. Sci. Adv. 6, eaax4001 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Chan, H. L. et al. Polycomb complexes associate with enhancers and promote oncogenic transcriptional programs in cancer through multiple mechanisms. Nat. Commun. 9, 3377 (2018).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  61. Ku, M. et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet. 4, e1000242 (2008).

    PubMed  PubMed Central  Google Scholar 

  62. Tanay, A., O’Donnell, A. H., Damelin, M. & Bestor, T. H. Hyperconserved CpG domains underlie Polycomb-binding sites. Proc. Natl Acad. Sci. USA 104, 5521–5526 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Schlesinger, Y. et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat. Genet. 39, 232–236 (2007).

    CAS  PubMed  Google Scholar 

  64. Bauer, M., Trupke, J. & Ringrose, L. The quest for mammalian Polycomb response elements: are we there yet? Chromosoma 125, 471–496 (2016).

    CAS  PubMed  Google Scholar 

  65. Kassis, J. A. & Brown, J. L. Polycomb group response elements in Drosophila and vertebrates. Adv. Genet. 81, 83–118 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Vella, P., Barozzi, I., Cuomo, A., Bonaldi, T. & Pasini, D. Yin Yang 1 extends the Myc-related transcription factors network in embryonic stem cells. Nucleic Acids Res. 40, 3403–3418 (2012).

    CAS  PubMed  Google Scholar 

  67. Endoh, M. et al. PCGF6-PRC1 suppresses premature differentiation of mouse embryonic stem cells by regulating germ cell-related genes. eLife 6, e21064 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. Trojer, P. et al. L3MBTL2 protein acts in concert with PcG protein-mediated monoubiquitination of H2A to establish a repressive chromatin structure. Mol. Cell 42, 438–450 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Ogawa, H., Ishiguro, K., Gaubatz, S., Livingston, D. M. & Nakatani, Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science 296, 1132–1136 (2002).

    CAS  PubMed  Google Scholar 

  70. Hurlin, P. J., Steingrimsson, E., Copeland, N. G., Jenkins, N. A. & Eisenman, R. N. Mga, a dual-specificity transcription factor that interacts with Max and contains a T-domain DNA-binding motif. EMBO J. 18, 7019–7028 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Stielow, B., Finkernagel, F., Stiewe, T., Nist, A. & Suske, G. MGA, L3MBTL2 and E2F6 determine genomic binding of the non-canonical Polycomb repressive complex PRC1.6. PLoS Genet. 14, e1007193 (2018).

    PubMed  PubMed Central  Google Scholar 

  72. Scelfo, A. et al. Functional landscape of PCGF proteins reveals both RING1A/B-dependent-and RING1A/B-independent-specific activities. Mol. Cell 74, 1037–1052 e1037 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Huang, Y. et al. Combinatorial control of recruitment of a variant PRC1.6 complex in embryonic stem cells. Cell Rep. 22, 3032–3043 (2018).

    CAS  PubMed  Google Scholar 

  74. Liu, M. et al. The polycomb group protein PCGF6 mediates germline gene silencing by recruiting histone-modifying proteins to target gene promoters. J. Biol. Chem. 295, 9712–9724 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhao, W. et al. Essential role for polycomb group protein Pcgf6 in embryonic stem cell maintenance and a noncanonical polycomb repressive complex 1 (PRC1) Integrity. J. Biol. Chem. 292, 2773–2784 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Yu, M. et al. Direct recruitment of polycomb repressive complex 1 to chromatin by core binding transcription factors. Mol. Cell 45, 330–343 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Ren, X. & Kerppola, T. K. REST interacts with Cbx proteins and regulates polycomb repressive complex 1 occupancy at RE1 elements. Mol. Cell Biol. 31, 2100–2110 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Herranz, N. et al. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol. Cell Biol. 28, 4772–4781 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Dietrich, N. et al. REST-mediated recruitment of polycomb repressor complexes in mammalian cells. PLoS Genet. 8, e1002494 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Almeida, M., Bowness, J. S. & Brockdorff, N. The many faces of Polycomb regulation by RNA. Curr. Opin. Genet. Dev. 61, 53–61 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Almeida, M. et al. PCGF3/5-PRC1 initiates Polycomb recruitment in X chromosome inactivation. Science 356, 1081–1084 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Pintacuda, G. et al. hnRNPK recruits PCGF3/5-PRC1 to the Xist RNA B-repeat to establish polycomb-mediated chromosomal silencing. Mol. Cell 68, 955–969 e910 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Chu, C. et al. Systematic discovery of Xist RNA binding proteins. Cell 161, 404–416 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Zylicz, J. J. et al. The implication of early chromatin changes in X chromosome inactivation. Cell 176, 182–197 e123 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Tsai, M. C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Somarowthu, S. et al. HOTAIR forms an intricate and modular secondary structure. Mol. Cell 58, 353–361 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Portoso, M. et al. PRC2 is dispensable for HOTAIR-mediated transcriptional repression. EMBO J. 36, 981–994 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Brockdorff, N. Noncoding RNA and Polycomb recruitment. RNA 19, 429–442 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Davidovich, C. & Cech, T. R. The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2. RNA 21, 2007–2022 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Pandey, R. R. et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol. Cell 32, 232–246 (2008).

    CAS  PubMed  Google Scholar 

  92. Regha, K. et al. Active and repressive chromatin are interspersed without spreading in an imprinted gene cluster in the mammalian genome. Mol. Cell 27, 353–366 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Schertzer, M. D. et al. lncRNA-induced spread of polycomb controlled by genome architecture, RNA abundance, and CpG island DNA. Mol. Cell 75, 523–537 e510 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen, Z. & Zhang, Y. Maternal H3K27me3-dependent autosomal and X chromosome imprinting. Nat. Rev. Genet. 21, 555–571 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Skourti-Stathaki, K. et al. R-loops enhance polycomb repression at a subset of developmental regulator genes. Mol. Cell 73, 930–945 e934 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen, P. B., Chen, H. V., Acharya, D., Rando, O. J. & Fazzio, T. G. R loops regulate promoter-proximal chromatin architecture and cellular differentiation. Nat. Struct. Mol. Biol. 22, 999–1007 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Saxonov, S., Berg, P. & Brutlag, D. L. A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc. Natl Acad. Sci. USA 103, 1412–1417 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Deaton, A. M. & Bird, A. CpG islands and the regulation of transcription. Genes Dev. 25, 1010–1022 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Illingworth, R. S. & Bird, A. P. CpG islands–‘a rough guide’. FEBS Lett. 583, 1713–1720 (2009).

    CAS  PubMed  Google Scholar 

  101. Schubeler, D. Function and information content of DNA methylation. Nature 517, 321–326 (2015).

    CAS  PubMed  Google Scholar 

  102. Garrick, D. et al. The role of the polycomb complex in silencing alpha-globin gene expression in nonerythroid cells. Blood 112, 3889–3899 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Gearhart, M. D., Corcoran, C. M., Wamstad, J. A. & Bardwell, V. J. Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol. Cell Biol. 26, 6880–6889 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Sanchez, C. et al. Proteomics analysis of Ring1B/Rnf2 interactors identifies a novel complex with the Fbxl10/Jhdm1B histone demethylase and the Bcl6 interacting corepressor. Mol. Cell Proteom. 6, 820–834 (2007).

    CAS  Google Scholar 

  105. Koyama-Nasu, R., David, G. & Tanese, N. The F-box protein Fbl10 is a novel transcriptional repressor of c-Jun. Nat. Cell Biol. 9, 1074–1080 (2007).

    CAS  PubMed  Google Scholar 

  106. Voo, K. S., Carlone, D. L., Jacobsen, B. M., Flodin, A. & Skalnik, D. G. Cloning of a mammalian transcriptional activator that binds unmethylated CpG motifs and shares a CXXC domain with DNA methyltransferase, human trithorax, and methyl-CpG binding domain protein 1. Mol. Cell Biol. 20, 2108–2121 (2000).

    CAS  PubMed  Google Scholar 

  107. Blackledge, N. P. et al. Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell 157, 1445–1459 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Farcas, A. M. et al. KDM2B links the polycomb repressive complex 1 (PRC1) to recognition of CpG islands. eLife 1, e00205 (2012).

    PubMed  PubMed Central  Google Scholar 

  109. He, J. et al. Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat. Cell Biol. 15, 373–384 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Wu, X., Johansen, J. V. & Helin, K. Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Mol. Cell 49, 1134–1146 (2013).

    CAS  PubMed  Google Scholar 

  111. Perino, M. et al. MTF2 recruits polycomb repressive complex 2 by helical-shape-selective DNA binding. Nat. Genet. 50, 1002–1010 (2018).

    CAS  PubMed  Google Scholar 

  112. Li, H. et al. Polycomb-like proteins link the PRC2 complex to CpG islands. Nature 549, 287–291 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Davidovich, C., Goodrich, K. J., Gooding, A. R. & Cech, T. R. A dimeric state for PRC2. Nucleic Acids Res. 42, 9236–9248 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Chen, S., Jiao, L., Liu, X., Yang, X. & Liu, X. A dimeric structural scaffold for PRC2-PCL targeting to CpG Island chromatin. Mol. Cell 77, 1265–1278 e1267 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Cooper, S. et al. Targeting polycomb to pericentric heterochromatin in embryonic stem cells reveals a role for H2AK119u1 in PRC2 recruitment. Cell Rep. 7, 1456–1470 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Cooper, S. et al. Jarid2 binds mono-ubiquitylated H2A lysine 119 to mediate crosstalk between Polycomb complexes PRC1 and PRC2. Nat. Commun. 7, 13661 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Kalb, R. et al. Histone H2A monoubiquitination promotes histone H3 methylation in Polycomb repression. Nat. Struct. Mol. Biol. 21, 569–571 (2014).

    CAS  PubMed  Google Scholar 

  118. Kasinath, V. et al. JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications. Science 371, eabc3393 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Blackledge, N. P. et al. PRC1 catalytic activity is central to polycomb system function. Mol. Cell 77, 857–874 e859 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Healy, E. et al. PRC2.1 and PRC2.2 Synergize to coordinate H3K27 trimethylation. Mol. Cell 76, 437–452 e436 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Hickey, G. J. M. et al. Establishment of developmental gene silencing by ordered polycomb complex recruitment in early zebrafish embryos. Preprint at bioRxiv https://doi.org/10.1101/2021.1103.1116.435592 (2021).

    Article  Google Scholar 

  123. Illingworth, R. S. et al. The E3 ubiquitin ligase activity of RING1B is not essential for early mouse development. Genes Dev. 29, 1897–1902 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  125. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Arrigoni, R. et al. The Polycomb-associated protein Rybp is a ubiquitin binding protein. FEBS Lett. 580, 6233–6241 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Lee, C. H. et al. Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin. Mol. Cell 70, 422–434 e426 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Oksuz, O. et al. Capturing the onset of PRC2-mediated repressive domain formation. Mol. Cell 70, 1149–1162 e1145 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Yuan, W. et al. Dense chromatin activates Polycomb repressive complex 2 to regulate H3 lysine 27 methylation. Science 337, 971–975 (2012).

    CAS  PubMed  Google Scholar 

  131. Min, J., Zhang, Y. & Xu, R. M. Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev. 17, 1823–1828 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang, L. et al. Hierarchical recruitment of polycomb group silencing complexes. Mol. Cell 14, 637–646 (2004).

    CAS  PubMed  Google Scholar 

  133. Cohen, I. et al. PRC1 fine-tunes gene repression and activation to safeguard skin development and stem cell specification. Cell Stem Cell 22, 726–-739 e727 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Moussa, H. F. et al. Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing. Nat. Commun. 10, 1931 (2019).

    PubMed  PubMed Central  Google Scholar 

  135. Schoenfelder, S. et al. Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome. Nat. Genet. 47, 1179–1186 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Vieux-Rochas, M., Fabre, P. J., Leleu, M., Duboule, D. & Noordermeer, D. Clustering of mammalian Hox genes with other H3K27me3 targets within an active nuclear domain. Proc. Natl Acad. Sci. USA 112, 4672–4677 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Bonev, B. et al. Multiscale 3D genome rewiring during mouse neural development. Cell 171, 557–572 e524 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Rhodes, J. D. P. et al. Cohesin disrupts polycomb-dependent chromosome interactions in embryonic stem cells. Cell Rep. 30, 820–835 e810 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. McLaughlin, K. et al. DNA methylation directs polycomb-dependent 3D genome re-organization in naive pluripotency. Cell Rep. 29, 1974–1985 e1976 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Bantignies, F. et al. Polycomb-dependent regulatory contacts between distant Hox loci in Drosophila. Cell 144, 214–226 (2011).

    CAS  PubMed  Google Scholar 

  142. Denholtz, M. et al. Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization. Cell Stem Cell 13, 602–616 (2013).

    CAS  PubMed  Google Scholar 

  143. Saurin, A. J. et al. The human polycomb group complex associates with pericentromeric heterochromatin to form a novel nuclear domain. J. Cell Biol. 142, 887–898 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Ren, X., Vincenz, C. & Kerppola, T. K. Changes in the distributions and dynamics of polycomb repressive complexes during embryonic stem cell differentiation. Mol. Cell Biol. 28, 2884–2895 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Satijn, D. P. et al. RING1 is associated with the polycomb group protein complex and acts as a transcriptional repressor. Mol. Cell Biol. 17, 4105–4113 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Kim, C. A., Gingery, M., Pilpa, R. M. & Bowie, J. U. The SAM domain of polyhomeotic forms a helical polymer. Nat. Struct. Biol. 9, 453–457 (2002).

    CAS  PubMed  Google Scholar 

  147. Boyle, S. et al. A central role for canonical PRC1 in shaping the 3D nuclear landscape. Genes Dev. 34, 931–949 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Isono, K. et al. SAM domain polymerization links subnuclear clustering of PRC1 to gene silencing. Dev. Cell 26, 565–577 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Wani, A. H. et al. Chromatin topology is coupled to Polycomb group protein subnuclear organization. Nat. Commun. 7, 10291 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Belaghzal, H. et al. Liquid chromatin Hi-C characterizes compartment-dependent chromatin interaction dynamics. Nat. Genet. 53, 367–378 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Huseyin, M. K. & Klose, R. J. Live-cell single particle tracking of PRC1 reveals a highly dynamic system with low target site occupancy. Nat. Commun. 12, 887 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Youmans, D. T., Schmidt, J. C. & Cech, T. R. Live-cell imaging reveals the dynamics of PRC2 and recruitment to chromatin by SUZ12-associated subunits. Genes Dev. 32, 794–805 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Zhen, C. Y. et al. Live-cell single-molecule tracking reveals co-recognition of H3K27me3 and DNA targets polycomb Cbx7-PRC1 to chromatin. eLife 5, e.17667 (2016).

    Google Scholar 

  155. Vandenbunder, B. et al. PRC1 components exhibit different binding kinetics in Polycomb bodies. Biol. Cell 106, 111–125 (2014).

    CAS  PubMed  Google Scholar 

  156. Cuadrado, A. et al. Specific contributions of cohesin-SA1 and cohesin-SA2 to TADs and polycomb domains in embryonic stem cells. Cell Rep. 27, 3500–3510 e3504 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Kriz, A. J., Colognori, D., Sunwoo, H., Nabet, B. & Lee, J. T. Balancing cohesin eviction and retention prevents aberrant chromosomal interactions, Polycomb-mediated repression, and X-inactivation. Mol. Cell 81, 1970–1987 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  160. Eeftens, J. M., Kapoor, M. & Brangwynne, C. P. Epigenetic memory as a time integral over prior history of Polycomb phase separation. Preprint at bioRxiv https://doi.org/10.1101/2020.1108.1119.254706 (2020).

    Article  Google Scholar 

  161. Seif, E. et al. Phase separation by the polyhomeotic sterile alpha motif compartmentalizes Polycomb group proteins and enhances their activity. Nat. Commun. 11, 5609 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).

    PubMed  Google Scholar 

  163. 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 e237 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Stewart-Morgan, K. R., Petryk, N. & Groth, A. Chromatin replication and epigenetic cell memory. Nat. Cell Biol. 22, 361–371 (2020).

    CAS  PubMed  Google Scholar 

  165. Escobar, T. M., Loyola, A. & Reinberg, D. Parental nucleosome segregation and the inheritance of cellular identity. Nat. Rev. Genet. 22, 379–392 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Reveron-Gomez, N. et al. Accurate recycling of parental histones reproduces the histone modification landscape during DNA replication. Mol. Cell 72, 239–249 e235 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Escobar, T. M. et al. Active and repressed chromatin domains exhibit distinct nucleosome segregation during DNA replication. Cell 179, 953–963 e911 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Reinberg, D. & Vales, L. D. Chromatin domains rich in inheritance. Science 361, 33–34 (2018).

    CAS  PubMed  Google Scholar 

  169. Alabert, C. et al. Domain model explains propagation dynamics and stability of histone H3K27 and H3K36 methylation landscapes. Cell Rep. 30, 1223–1234 e1228 (2020).

    CAS  PubMed  Google Scholar 

  170. Alabert, C. et al. Two distinct modes for propagation of histone PTMs across the cell cycle. Genes Dev. 29, 585–590 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Hansen, K. H. et al. A model for transmission of the H3K27me3 epigenetic mark. Nat. Cell Biol. 10, 1291–1300 (2008).

    CAS  PubMed  Google Scholar 

  172. Hojfeldt, J. W. et al. Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2. Nat. Struct. Mol. Biol. 25, 225–232 (2018).

    PubMed  PubMed Central  Google Scholar 

  173. Laprell, F., Finkl, K. & Muller, J. Propagation of Polycomb-repressed chromatin requires sequence-specific recruitment to DNA. Science 356, 85–88 (2017).

    CAS  PubMed  Google Scholar 

  174. 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).

    PubMed  PubMed Central  Google Scholar 

  175. Smith, E. & Shilatifard, A. The chromatin signaling pathway: diverse mechanisms of recruitment of histone-modifying enzymes and varied biological outcomes. Mol. Cell 40, 689–701 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Kloet, S. L. et al. The dynamic interactome and genomic targets of Polycomb complexes during stem-cell differentiation. Nat. Struct. Mol. Biol. 23, 682–690 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Morey, L., Aloia, L., Cozzuto, L., Benitah, S. A. & Di Croce, L. RYBP and Cbx7 define specific biological functions of polycomb complexes in mouse embryonic stem cells. Cell Rep. 3, 60–69 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  179. Kaneko, S., Son, J., Bonasio, R., Shen, S. S. & Reinberg, D. Nascent RNA interaction keeps PRC2 activity poised and in check. Genes Dev. 28, 1983–1988 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Jermann, P., Hoerner, L., Burger, L. & Schubeler, D. Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation. Proc. Natl Acad. Sci. USA 111, E3415–E3421 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Lynch, M. D. et al. An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J. 31, 317–329 (2012).

    CAS  PubMed  Google Scholar 

  182. Hosogane, M., Funayama, R., Nishida, Y., Nagashima, T. & Nakayama, K. Ras-induced changes in H3K27me3 occur after those in transcriptional activity. PLoS Genet. 9, e1003698 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Zhao, J. et al. Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol. Cell 40, 939–953 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Kaneko, S., Son, J., Shen, S. S., Reinberg, D. & Bonasio, R. PRC2 binds active promoters and contacts nascent RNAs in embryonic stem cells. Nat. Struct. Mol. Biol. 20, 1258–1264 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Wang, X. et al. Targeting of polycomb repressive complex 2 to RNA by short repeats of consecutive guanines. Mol. Cell 65, 1056–1067 e1055 (2017).

    CAS  PubMed  Google Scholar 

  186. Long, Y. et al. Conserved RNA-binding specificity of polycomb repressive complex 2 is achieved by dispersed amino acid patches in EZH2. eLife 6, e.31558 (2017).

    Google Scholar 

  187. Kanhere, A. et al. Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. Mol. Cell 38, 675–688 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Davidovich, C., Zheng, L., Goodrich, K. J. & Cech, T. R. Promiscuous RNA binding by Polycomb repressive complex 2. Nat. Struct. Mol. Biol. 20, 1250–1257 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Davidovich, C. et al. Toward a consensus on the binding specificity and promiscuity of PRC2 for RNA. Mol. Cell 57, 552–558 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Beltran, M. et al. G-tract RNA removes polycomb repressive complex 2 from genes. Nat. Struct. Mol. Biol. 26, 899–909 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Beltran, M. et al. The interaction of PRC2 with RNA or chromatin is mutually antagonistic. Genome Res. 26, 896–907 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Wang, X. et al. Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA. Nat. Struct. Mol. Biol. 24, 1028–1038 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Zhang, Q. et al. RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2. Nat. Struct. Mol. Biol. 26, 237–247 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Long, Y. et al. RNA is essential for PRC2 chromatin occupancy and function in human pluripotent stem cells. Nat. Genet. 52, 931–938 (2020).

    CAS  PubMed  Google Scholar 

  195. Wei, C. et al. RBFox2 binds Nascent RNA to globally regulate polycomb complex 2 targeting in mammalian genomes. Mol. Cell 62, 875–889 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  197. Jani, K. S. et al. Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase. Proc. Natl Acad. Sci. USA 1+16, 8295–8300 (2019).

    Google Scholar 

  198. Schmitges, F. W. et al. Histone methylation by PRC2 is inhibited by active chromatin marks. Mol. Cell 42, 330–341 (2011).

    CAS  PubMed  Google Scholar 

  199. Streubel, G. et al. The H3K36me2 methyltransferase Nsd1 demarcates PRC2-mediated H3K27me2 and H3K27me3 domains in embryonic stem cells. Mol. Cell 70, 371–379 e375 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Yuan, W. et al. H3K36 methylation antagonizes PRC2-mediated H3K27 methylation. J. Biol. Chem. 286, 7983–7989 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Xu, Q. et al. SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development. Nat. Genet. 51, 844–856 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  204. Agger, K. et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449, 731–734 (2007).

    CAS  PubMed  Google Scholar 

  205. Chen, S. et al. The histone H3 Lys 27 demethylase JMJD3 regulates gene expression by impacting transcriptional elongation. Genes Dev. 26, 1364–1375 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. De Santa, F. et al. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130, 1083–1094 (2007).

    PubMed  Google Scholar 

  207. Vernimmen, D. et al. Polycomb eviction as a new distant enhancer function. Genes Dev. 25, 1583–1588 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Williams, K. et al. The histone lysine demethylase JMJD3/KDM6B is recruited to p53 bound promoters and enhancer elements in a p53 dependent manner. PLoS ONE 9, e96545 (2014).

    PubMed  PubMed Central  Google Scholar 

  209. Lee, M. G. et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318, 447–450 (2007).

    CAS  PubMed  Google Scholar 

  210. Tie, F. et al. CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development 136, 3131–3141 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Weaver, T. M. et al. The EZH2 SANT1 domain is a histone reader providing sensitivity to the modification state of the H4 tail. Sci. Rep. 9, 987 (2019).

    PubMed  PubMed Central  Google Scholar 

  212. Pasini, D. et al. Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes. Nucleic Acids Res. 38, 4958–4969 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Reynolds, N. et al. NuRD-mediated deacetylation of H3K27 facilitates recruitment of Polycomb repressive complex 2 to direct gene repression. EMBO J. 31, 593–605 (2012).

    CAS  PubMed  Google Scholar 

  214. Kim, T. W. et al. Ctbp2 modulates NuRD-mediated deacetylation of H3K27 and facilitates PRC2-mediated H3K27me3 in active embryonic stem cell genes during exit from pluripotency. Stem Cell 33, 2442–2455 (2015).

    CAS  Google Scholar 

  215. Lavarone, E., Barbieri, C. M. & Pasini, D. Dissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity. Nat. Commun. 10, 1679 (2019).

    PubMed  PubMed Central  Google Scholar 

  216. Zhu, P. et al. A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation. Mol. Cell 27, 609–621 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Yang, W. et al. The histone H2A deubiquitinase Usp16 regulates embryonic stem cell gene expression and lineage commitment. Nat. Commun. 5, 3818 (2014).

    CAS  PubMed  Google Scholar 

  218. Ho, L. et al. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nat. Cell Biol. 13, 903–913 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Kadoch, C. et al. Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat. Genet. 49, 213–222 (2017).

    CAS  PubMed  Google Scholar 

  220. Weber, C. M. et al. mSWI/SNF promotes polycomb repression both directly and through genome-wide redistribution. Nat. Struct. Mol. Biol. 28, 501–511 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Stanton, B. Z. et al. Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. Nat. Genet. 49, 282–288 (2017).

    CAS  PubMed  Google Scholar 

  222. Klose, R. J., Cooper, S., Farcas, A. M., Blackledge, N. P. & Brockdorff, N. Chromatin sampling–an emerging perspective on targeting polycomb repressor proteins. PLoS Genet. 9, e1003717 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Jones, R. S. & Gelbart, W. M. Genetic analysis of the enhancer of zeste locus and its role in gene regulation in Drosophila melanogaster. Genetics 126, 185–199 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Struhl, G. & Akam, M. Altered distributions of Ultrabithorax transcripts in extra sex combs mutant embryos of Drosophila. EMBO J. 4, 3259–3264 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Akasaka, T. et al. Mice doubly deficient for the Polycomb group genes Mel18 and Bmi1 reveal synergy and requirement for maintenance but not initiation of Hox gene expression. Development 128, 1587–1597 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  227. Grau, D. J. et al. Compaction of chromatin by diverse Polycomb group proteins requires localized regions of high charge. Genes Dev. 25, 2210–2221 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Lau, M. S. et al. Mutation of a nucleosome compaction region disrupts Polycomb-mediated axial patterning. Science 355, 1081–1084 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Forzati, F. et al. CBX7 is a tumor suppressor in mice and humans. J. Clin. Invest. 122, 612–623 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Pirity, M. K., Locker, J. & Schreiber-Agus, N. Rybp/DEDAF is required for early postimplantation and for central nervous system development. Mol. Cell Biol. 25, 7193–7202 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. King, H. W., Fursova, N. A., Blackledge, N. P. & Klose, R. J. Polycomb repressive complex 1 shapes the nucleosome landscape but not accessibility at target genes. Genome Res. 28, 1494–1507 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Hodges, H. C. et al. Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat. Struct. Mol. Biol. 25, 61–72 (2018).

    CAS  PubMed  Google Scholar 

  233. Dobrinić, P., Szczurek, A. T. & Klose, R. J. PRC1 drives Polycomb-mediated gene repression by controlling transcription initiation and burst frequency. Preprint at bioRxiv https://doi.org/10.1101/2020.1110.1109.333294 (2020).

    Article  Google Scholar 

  234. Zhang, Z. et al. Role of remodeling and spacing factor 1 in histone H2A ubiquitination-mediated gene silencing. Proc. Natl Acad. Sci. USA 114, E7949–E7958 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Nakagawa, T. et al. Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di- and trimethylation. Genes Dev. 22, 37–49 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Aihara, H. et al. Histone H2A T120 phosphorylation promotes oncogenic transformation via upregulation of cyclin D1. Mol. Cell 64, 176–188 (2016).

    CAS  PubMed  Google Scholar 

  237. Lehmann, L. et al. Polycomb repressive complex 1 (PRC1) disassembles RNA polymerase II preinitiation complexes. J. Biol. Chem. 287, 35784–35794 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Dellino, G. I. et al. Polycomb silencing blocks transcription initiation. Mol. Cell 13, 887–893 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  240. Brookes, E. et al. Polycomb associates genome-wide with a specific RNA polymerase II variant, and regulates metabolic genes in ESCs. Cell Stem Cell 10, 157–170 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Tsuboi, M. et al. Ubiquitination-independent repression of PRC1 targets during neuronal fate restriction in the developing mouse neocortex. Dev. Cell 47, 758–772 e755 (2018).

    CAS  PubMed  Google Scholar 

  242. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Posfai, E. et al. Polycomb function during oogenesis is required for mouse embryonic development. Genes Dev. 26, 920–932 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Pasini, D., Bracken, A. P., Jensen, M. R., Lazzerini Denchi, E. & Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23, 4061–4071 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Endoh, M. et al. Polycomb group proteins Ring1A/B are functionally linked to the core transcriptional regulatory circuitry to maintain ES cell identity. Development 135, 1513–1524 (2008).

    CAS  PubMed  Google Scholar 

  246. Cohen, I. et al. PRC1 preserves epidermal tissue integrity independently of PRC2. Genes Dev. 33, 55–60 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Chiacchiera, F., Rossi, A., Jammula, S., Zanotti, M. & Pasini, D. PRC2 preserves intestinal progenitors and restricts secretory lineage commitment. EMBO J. 35, 2301–2314 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Chiacchiera, F. et al. Polycomb complex PRC1 preserves intestinal stem cell identity by sustaining Wnt/beta-catenin transcriptional activity. Cell Stem Cell 18, 91–103 (2016).

    CAS  PubMed  Google Scholar 

  249. 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).

    CAS  PubMed  Google Scholar 

  250. Stepanik, V. A. & Harte, P. J. A mutation in the E(Z) methyltransferase that increases trimethylation of histone H3 lysine 27 and causes inappropriate silencing of active Polycomb target genes. Dev. Biol. 364, 249–258 (2012).

    CAS  PubMed  Google Scholar 

  251. Bradley, W. D. et al. EZH2 inhibitor efficacy in non-Hodgkin’s lymphoma does not require suppression of H3K27 monomethylation. Chem. Biol. 21, 1463–1475 (2014).

    CAS  PubMed  Google Scholar 

  252. Jadhav, U. et al. Replicational dilution of H3K27me3 in mammalian cells and the role of poised promoters. Mol. Cell 78, 141–151 e145 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Fan, H. et al. A conserved BAH module within mammalian BAHD1 connects H3K27me3 to Polycomb gene silencing. Nucleic Acids Res. 49, 4441–4455 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. Zhao, D. et al. The BAH domain of BAHD1 is a histone H3K27me3 reader. Protein Cell 7, 222–226 (2016).

    PubMed  PubMed Central  Google Scholar 

  255. Xu, P. et al. FBXO11-mediated proteolysis of BAHD1 relieves PRC2-dependent transcriptional repression in erythropoiesis. Blood 137, 155–167 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Ardehali, M. B. et al. Polycomb repressive complex 2 methylates elongin A to regulate transcription. Mol. Cell 68, 872–884 e876 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. He, A. et al. PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes Dev. 26, 37–42 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Zepeda-Martinez, J. A. et al. Parallel PRC2/cPRC1 and vPRC1 pathways silence lineage-specific genes and maintain self-renewal in mouse embryonic stem cells. Sci. Adv. 6, eaax5692 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Cohen, I. et al. Polycomb complexes redundantly maintain epidermal stem cell identity during development. Genes Dev. 35, 354–366 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Leeb, M. et al. Polycomb complexes act redundantly to repress genomic repeats and genes. Genes Dev. 24, 265–276 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Inoue, A., Jiang, L., Lu, F., Suzuki, T. & Zhang, Y. Maternal H3K27me3 controls DNA methylation-independent imprinting. Nature 547, 419–424 (2017).

    CAS  PubMed  Google Scholar 

  262. Beguelin, W. et al. EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and lymphomagenesis. Cancer Cell 30, 197–213 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  263. Klauke, K. et al. Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat. Cell Biol. 15, 353–362 (2013).

    CAS  PubMed  Google Scholar 

  264. Morey, L. et al. Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells. Cell Stem Cell 10, 47–62 (2012).

    CAS  PubMed  Google Scholar 

  265. O’Loghlen, A. et al. MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation. Cell Stem Cell 10, 33–46 (2012).

    PubMed  PubMed Central  Google Scholar 

  266. Matsui, S. I., Seon, B. K. & Sandberg, A. A. Disappearance of a structural chromatin protein A24 in mitosis: implications for molecular basis of chromatin condensation. Proc. Natl Acad. Sci. USA 76, 6386–6390 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  267. Pena-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44, 751–759 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. Scheuermann, J. C. et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465, 243–247 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Campagne, A. et al. BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation. Nat. Commun. 10, 348 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Conway, E. et al. BAP1 enhances polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation. Mol. Cell 81, 1–16 (2021).

    Google Scholar 

  271. Fursova, N. A. et al. BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome. Genes Dev. 35, 749–770 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  272. Ferrari, K. J. et al. Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity. Mol. Cell 53, 49–62 (2014).

    CAS  PubMed  Google Scholar 

  273. Grzybowski, A. T., Chen, Z. & Ruthenburg, A. J. Calibrating ChIP-seq with nucleosomal internal standards to measure histone modification density genome wide. Mol. Cell 58, 886–899 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. Hojfeldt, J. W. et al. Non-core subunits of the PRC2 complex are collectively required for its target-site specificity. Mol. Cell 76, 423–436 e423 (2019).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  276. Lee, H. G., Kahn, T. G., Simcox, A., Schwartz, Y. B. & Pirrotta, V. Genome-wide activities of Polycomb complexes control pervasive transcription. Genome Res. 25, 1170–1181 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Du, Z. et al. Polycomb group proteins regulate chromatin architecture in mouse oocytes and early embryos. Mol. Cell 77, 825–839 e827 (2020).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  279. Gao, Z. et al. An AUTS2-Polycomb complex activates gene expression in the CNS. Nature 516, 349–354 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  280. Frangini, A. et al. The aurora B kinase and the polycomb protein ring1B combine to regulate active promoters in quiescent lymphocytes. Mol. Cell 51, 647–661 (2013).

    CAS  PubMed  Google Scholar 

  281. Creppe, C., Palau, A., Malinverni, R., Valero, V. & Buschbeck, M. A Cbx8-containing polycomb complex facilitates the transition to gene activation during ES cell differentiation. PLoS Genet. 10, e1004851 (2014).

    PubMed  PubMed Central  Google Scholar 

  282. Maezawa, S. et al. Polycomb directs timely activation of germline genes in spermatogenesis. Genes Dev. 31, 1693–1703 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Richly, H. et al. Transcriptional activation of polycomb-repressed genes by ZRF1. Nature 468, 1124–1128 (2010).

    CAS  PubMed  Google Scholar 

  284. Cruz-Molina, S. et al. PRC2 facilitates the regulatory topology required for poised enhancer function during pluripotent stem cell differentiation. Cell Stem Cell 20, 689–705 e689 (2017).

    CAS  PubMed  Google Scholar 

  285. Kondo, T. et al. Polycomb potentiates meis2 activation in midbrain by mediating interaction of the promoter with a tissue-specific enhancer. Dev. Cell 28, 94–101 (2014).

    CAS  PubMed  Google Scholar 

  286. Pachano, T. et al. Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness. Nat. Genet. https://doi.org/10.1038/s41588-021-00888-x (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  287. Morey, L. et al. Polycomb regulates mesoderm cell fate-specification in embryonic stem cells through activation and repression mechanisms. Cell Stem Cell 17, 300–315 (2015).

    CAS  PubMed  Google Scholar 

  288. Mohn, F. et al. Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol. Cell 30, 755–766 (2008).

    CAS  PubMed  Google Scholar 

  289. Xie, R. et al. Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell 12, 224–237 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  290. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. Ebmeier, C. C. et al. Human TFIIH kinase CDK7 regulates transcription-associated chromatin modifications. Cell Rep. 20, 1173–1186 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  292. Lee, J. H. & Skalnik, D. G. Wdr82 is a C-terminal domain-binding protein that recruits the Setd1A histone H3-Lys4 methyltransferase complex to transcription start sites of transcribed human genes. Mol. Cell Biol. 28, 609–618 (2008).

    CAS  PubMed  Google Scholar 

  293. Eberl, H. C., Spruijt, C. G., Kelstrup, C. D., Vermeulen, M. & Mann, M. A map of general and specialized chromatin readers in mouse tissues generated by label-free interaction proteomics. Mol. Cell 49, 368–378 (2013).

    CAS  PubMed  Google Scholar 

  294. Brown, D. A. et al. The SET1 complex selects actively transcribed target genes via multivalent interaction with CpG island chromatin. Cell Rep. 20, 2313–2327 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  295. Clouaire, T. et al. Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells. Genes Dev. 26, 1714–1728 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  297. Reinig, J., Ruge, F., Howard, M. & Ringrose, L. A theoretical model of Polycomb/Trithorax action unites stable epigenetic memory and dynamic regulation. Nat. Commun. 11, 4782 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  298. Sneppen, K. & Ringrose, L. Theoretical analysis of Polycomb-Trithorax systems predicts that poised chromatin is bistable and not bivalent. Nat. Commun. 10, 2133 (2019).

    PubMed  PubMed Central  Google Scholar 

  299. Voigt, P., Tee, W. W. & Reinberg, D. A double take on bivalent promoters. Genes Dev. 27, 1318–1338 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  300. Binder, H. et al. Transcriptional regulation by histone modifications: towards a theory of chromatin re-organization during stem cell differentiation. Phys. Biol. 10, 026006 (2013).

    CAS  PubMed  Google Scholar 

  301. Yakushiji-Kaminatsui, N. et al. Variant PRC1 competes with retinoic acid-related signals to repress Meis2 in the mouse distal forelimb bud. Development 145, dev166348 (2018).

    PubMed  Google Scholar 

  302. Angel, A., Song, J., Dean, C. & Howard, M. A Polycomb-based switch underlying quantitative epigenetic memory. Nature 476, 105–108 (2011).

    CAS  PubMed  Google Scholar 

  303. Berry, S., Dean, C. & Howard, M. Slow chromatin dynamics allow polycomb target genes to filter fluctuations in transcription factor activity. Cell Syst. 4, 445–457 e448 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  304. Kar, G. et al. Flipping between Polycomb repressed and active transcriptional states introduces noise in gene expression. Nat. Commun. 8, 36 (2017).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  306. Rosen, G. A. et al. Dynamics of RNA polymerase II and elongation factor Spt4/5 recruitment during activator-dependent transcription. Proc. Natl Acad. Sci. USA 117, 32348–32357 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  307. Friedman, L. J. & Gelles, J. Mechanism of transcription initiation at an activator-dependent promoter defined by single-molecule observation. Cell 148, 679–689 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank N. Fursova, E. Dimitrova, M. Huseyin, P. Dobrinić and T. Milne for critical reading of the manuscript. Work in the Klose laboratory is supported by the Wellcome Trust (209400/Z/17/Z) and the European Research Council (681440).

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Neil P. Blackledge or Robert J. Klose.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks Oliver Bell, who co-reviewed with Daniel Bsteh, Elena Ezhkova and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blackledge, N.P., Klose, R.J. The molecular principles of gene regulation by Polycomb repressive complexes. Nat Rev Mol Cell Biol 22, 815–833 (2021). https://doi.org/10.1038/s41580-021-00398-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-021-00398-y

This article is cited by

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