Epigenetic balance of gene expression by polycomb and compass families

Science

Volumn 352, Issue 6290, 2016, Pages

  Piunti, Andrea ^a   Shilatifard, Ali ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BMI1 PROTEIN; POLYCOMB REPRESSIVE COMPLEX 2; CHROMATIN; HISTONE; HISTONE LYSINE METHYLTRANSFERASE; NONHISTONE PROTEIN; POLYCOMB GROUP PROTEIN;

CHROMATE; DEREGULATION; GENE EXPRESSION; METAZOAN; MUTATION; PATHOLOGY; PROTEIN;

CELL DIFFERENTIATION; CHROMATIN; DROSOPHILA; ENHANCER REGION; EPIGENETICS; GENE EXPRESSION; LEUKEMOGENESIS; MALIGNANT NEOPLASTIC DISEASE; MUTATION; NONHUMAN; ONCOGENE; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN METHYLATION; REVIEW; TRANSCRIPTION ELONGATION; ANIMAL; DROSOPHILA MELANOGASTER; EMBRYO DEVELOPMENT; GENETIC EPIGENESIS; GENETICS; GROWTH, DEVELOPMENT AND AGING; HUMAN; METABOLISM; METHYLATION; NEOPLASM; SACCHAROMYCES CEREVISIAE;

METAZOA;

ANIMALS; CHROMATIN; CHROMOSOMAL PROTEINS, NON-HISTONE; DROSOPHILA MELANOGASTER; EMBRYONIC DEVELOPMENT; ENHANCER ELEMENTS, GENETIC; EPIGENESIS, GENETIC; GENE EXPRESSION; GROWTH AND DEVELOPMENT; HISTONE-LYSINE N-METHYLTRANSFERASE; HISTONES; HUMANS; METHYLATION; MUTATION; NEOPLASMS; POLYCOMB-GROUP PROTEINS; SACCHAROMYCES CEREVISIAE;

EID: 84974693469     PISSN: 00368075     EISSN: 10959203     Source Type: Journal    
DOI: 10.1126/science.aad9780     Document Type: Review

References (243)

1. R. Jaenisch, A. Bird, Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat. Genet. 33 (Suppl), 245-254 (2003).doi: 10.1038/ng1089; pmid: 12610534
2. R. D. Kornberg, Y. Lorch, Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98, 285-294 (1999). doi: 10.1016/S0092-8674(00)81958-3; pmid: 10458604
3. A. J. Bannister, T. Kouzarides, Regulation of chromatin by histone modifications. Cell Res. 21, 381-395 (2011).doi: 10.1038/cr.2011.22; pmid: 21321607
4. P. A. Steffen, L. Ringrose, What are memories made of? How Polycomb and Trithorax proteins mediate epigenetic memory. Nat. Rev. Mol. Cell Biol. 15, 340-356 (2014).doi: 10.1038/nrm3789; pmid: 24755934
5. A. Shilatifard, The COMPASS family of histone H3K4 methylases: Mechanisms of regulation in development and disease pathogenesis. Annu. Rev. Biochem. 81, 65-95 (2012).doi: 10.1146/annurev-biochem-051710-134100; pmid: 22663077
6. B. Schuettengruber, D. Chourrout, M. Vervoort, B. Leblanc, G. Cavalli, Genome regulation by Polycomb and Trithorax proteins. Cell 128, 735-745 (2007). doi: 10.1016/ j.cell.2007.02.009; pmid: 17320510
7. P. W. Ingham, trithorax and the regulation of homeotic gene expression in Drosophila: A historical perspective. Int. J. Dev. Biol. 42, 423-429 (1998). pmid: 9654027
8. P. W. Ingham, Differential expression of bithorax complex genes in the absence of the extra sex combs and trithorax genes. Nature 306, 591-593 (1983). doi: 10.1038/306591a0; pmid: 24937863
9. J. W. Tamkun et al., brahma: A regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68, 561-572 (1992). doi: 10.1016/0092-8674(92)90191-E; pmid: 1346755
10. P. Filippakopoulos, S. Knapp, Targeting bromodomains: Epigenetic readers of lysine acetylation. Nat. Rev. Drug Discov. 13, 337-356 (2014). doi: 10.1038/nrd4286; pmid: 24751816
11. J. Simon, Locking in stable states of gene expression: Transcriptional control during Drosophila development. Curr. Opin. Cell Biol. 7, 376-385 (1995). doi: 10.1016/ 0955-0674(95)80093-X; pmid: 7662368
12. P. H. Lewis, New mutants report. Drosoph. Inf. Serv. 21, 69 (1947).
13. J. Puro, T. Nygrén, Mode of action of a homoeotic gene in Drosophila melanogaster. Localization and dosage effects of Polycomb. Hereditas 81, 237-247 (1975). doi: 10.1111/j.1601-5223.1975.tb01038.x; pmid: 814109
14. E. B. Lewis, A gene complex controlling segmentation in Drosophila. Nature 276, 565-570 (1978). doi: 10.1038/276565a0; pmid: 103000
15. A. A. Mills, Throwing the cancer switch: Reciprocal roles of polycomb and trithorax proteins. Nat. Rev. Cancer 10, 669-682 (2010). doi: 10.1038/nrc2931; pmid: 20865010
16. J. A. Kennison, The Polycomb and trithorax group proteins of Drosophila: Trans-regulators of homeotic gene function. Annu. Rev. Genet. 29, 289-303 (1995). doi: 10.1146/annurev. ge.29.120195.001445; pmid: 8825476
17. A. Shilatifard, Chromatin modifications by methylation and ubiquitination: Implications in the regulation of gene expression. Annu. Rev. Biochem. 75, 243-269 (2006).doi: 10.1146/annurev.biochem.75.103004.142422; pmid: 16756492
18. K. Jamieson, M. R. Rountree, Z. A. Lewis, J. E. Stajich, E. U. Selker, Regional control of histone H3 lysine 27 methylation in Neurospora. Proc. Natl. Acad. Sci. U.S.A. 110, 6027-6032 (2013). doi: 10.1073/pnas.1303750110; pmid: 23530226
19. P. A. Dumesic et al., Product binding enforces the genomic specificity of a yeast Polycomb repressive complex. Cell 160, 204-218 (2015). doi: 10.1016/j.cell.2014.11.039; pmid: 25533783
20. S. Ziemin-van der Poel et al., Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. Proc. Natl. Acad. Sci. U.S.A. 88, 10735-10739 (1991). doi: 10.1073/pnas.88.23.10735; pmid: 1720549
21. T. Miller et al., COMPASS: A complex of proteins associated with a trithorax-related SET domain protein. Proc. Natl. Acad. Sci. U.S.A. 98, 12902-12907 (2001). doi: 10.1073/ pnas.231473398; pmid: 11687631
22. N. J. Krogan et al., COMPASS, a histone H3 (Lysine 4) methyltransferase required for telomeric silencing of gene expression. J. Biol. Chem. 277, 10753-10755 (2002).doi: 10.1074/jbc.C200023200; pmid: 11805083
23. J. C. Eissenberg, A. Shilatifard, Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev. Biol. 339, 240-249 (2010). doi: 10.1016/j.ydbio.2009.08.017; pmid: 19703438
24. M. Mohan et al., The COMPASS family of H3K4 methylases in Drosophila. Mol. Cell. Biol. 31, 4310-4318 (2011).doi: 10.1128/MCB.06092-11; pmid: 21875999
25. H. M. Herz et al., Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev. 26, 2604-2620 (2012). doi: 10.1101/gad.201327.112; pmid: 23166019
26. M. B. Ardehali et al., Drosophila Set1 is the major histone H3 lysine 4 trimethyltransferase with role in transcription. EMBO J. 30, 2817-2828 (2011). doi: 10.1038/emboj.2011.194; pmid: 21694722
27. S. Petruk et al., Transcription of bxd noncoding RNAs promoted by trithorax represses Ubx in cis by transcriptional interference. Cell 127, 1209-1221 (2006). doi: 10.1016/ j.cell.2006.10.039; pmid: 17174895
28. L. Ringrose, R. Paro, Polycomb/Trithorax response elements and epigenetic memory of cell identity. Development 134, 223-232 (2007). doi: 10.1242/dev.02723; pmid: 17185323
29. M. Gerber, A. Shilatifard, Transcriptional elongation by RNA polymerase II and histone methylation. J. Biol. Chem. 278, 26303-26306 (2003). doi: 10.1074/jbc.R300014200; pmid: 12764140
30. H. M. Herz, D. Hu, A. Shilatifard, Enhancer malfunction in cancer. Mol. Cell 53, 859-866 (2014). doi: 10.1016/ j.molcel.2014.02.033; pmid: 24656127
31. E. Smith, A. Shilatifard, Enhancer biology and enhanceropathies. Nat. Struct. Mol. Biol. 21, 210-219 (2014).doi: 10.1038/nsmb.2784; pmid: 24599251
32. C. Benoist, P. Chambon, In vivo sequence requirements of the SV40 early promotor region. Nature 290, 304-310 (1981). doi: 10.1038/290304a0; pmid: 6259538
33. Y. Shen et al., A map of the cis-regulatory sequences in the mouse genome. Nature 488, 116-120 (2012). doi: 10.1038/ nature11243; pmid: 22763441
34. M. P. Creyghton et al., Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl. Acad. Sci. U.S.A.107, 21931-21936 (2010). doi: 10.1073/pnas.1016071107; pmid: 21106759
35. D. Shlyueva, G. Stampfel, A. Stark, Transcriptional enhancers: From properties to genome-wide predictions. Nat. Rev. Genet. 15, 272-286 (2014). doi: 10.1038/nrg3682; pmid: 24614317
36. D. Hu et al., The Mll2 branch of the COMPASS family regulates bivalent promoters in mouse embryonic stem cells. Nat. Struct. Mol. Biol. 20, 1093-1097 (2013). doi: 10.1038/ nsmb.2653; pmid: 23934151
37. M. M. Steward et al., Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nat. Struct. Mol. Biol. 13, 852-854 (2006).doi: 10.1038/nsmb1131; pmid: 16892064
38. Y. Dou et al., Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat. Struct. Mol. Biol. 13, 713-719 (2006). doi: 10.1038/nsmb1128; pmid: 16878130
39. M. Wu et al., Molecular regulation of H3K4 trimethylation by Wdr82, a component of human Set1/COMPASS. Mol. Cell. Biol. 28, 7337-7344 (2008). doi: 10.1128/MCB.00976-08; pmid: 18838538
40. K. T. FitzGerald, M. O. Diaz, MLL2: A new mammalian member of the trx/MLL family of genes. Genomics 59, 187-192 (1999). doi: 10.1006/geno.1999.5860; pmid: 10409430
41. Y. Dou et al., Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121, 873-885 (2005).doi: 10.1016/j.cell.2005.04.031; pmid: 15960975
42. H. Jiang et al., Regulation of transcription by the MLL2 complex and MLL complex-associated AKAP95. Nat. Struct. Mol. Biol. 20, 1156-1163 (2013). doi: 10.1038/nsmb.2656; pmid: 23995757
43. S. Denissov et al., Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant. Development 141, 526-537 (2014). doi: 10.1242/ dev.102681; pmid: 24423662
44. D. Hu et al., The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol. Cell. Biol. 33, 4745-4754 (2013).doi: 10.1128/MCB.01181-13; pmid: 24081332
45. J. Cheng et al., A role for H3K4 monomethylation in gene repression and partitioning of chromatin readers. Mol. Cell 53, 979-992 (2014). doi: 10.1016/j.molcel.2014.02.032; pmid: 24656132
46. A. Scelfo, A. Piunti, D. Pasini, The controversial role of the Polycomb group proteins in transcription and cancer: How much do we not understand Polycomb proteins? FEBS J. 282, 1703-1722 (2015). doi: 10.1111/febs.13112; pmid: 25315766
47. S. Aranda, G. Mas, L. Di Croce, Regulation of gene transcription by Polycomb proteins. Sci. Adv. 1, e1500737 (2015). doi: 10.1126/sciadv.1500737; pmid: 26665172
48. R. Margueron, D. Reinberg, The Polycomb complex PRC2 and its mark in life. Nature 469, 343-349 (2011). doi: 10.1038/ nature09784; pmid: 21248841
49. R. Cao, Y. Zhang, SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol. Cell 15, 57-67 (2004). doi: 10.1016/ j.molcel.2004.06.020; pmid: 15225548
50. D. Pasini, A. P. Bracken, M. R. Jensen, E. L. Denchi, K. Helin, Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23, 4061-4071 (2004). doi: 10.1038/sj.emboj.7600402; pmid: 15385962
51. R. Cao et al., Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039-1043 (2002).doi: 10.1126/science.1076997; pmid: 12351676
52. M. Nekrasov, B. Wild, J. Müller, Nucleosome binding and histone methyltransferase activity of Drosophila PRC2. EMBO Rep. 6, 348-353 (2005). doi: 10.1038/sj.embor.7400376; pmid: 15776017
53. E. Walker et al., Polycomb-like 2 associates with PRC2 and regulates transcriptional networks during mouse embryonic stem cell self-renewal and differentiation. Cell Stem Cell 6, 153-166 (2010). doi: 10.1016/j.stem.2009.12.014; pmid: 20144788
54. D. Pasini et al., JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464, 306-310 (2010). doi: 10.1038/nature08788; pmid: 20075857
55. J. C. Peng et al., Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell 139, 1290-1302 (2009). doi: 10.1016/ j.cell.2009.12.002; pmid: 20064375
56. X. Shen et al., Jumonji modulates polycomb activity and selfrenewal versus differentiation of stem cells. Cell 139, 1303-1314 (2009). doi: 10.1016/j.cell.2009.12.003; pmid: 20064376
57. S. Sanulli et al., Jarid2 Methylation via the PRC2 Complex Regulates H3K27me3 Deposition during Cell Differentiation. Mol. Cell 57, 769-783 (2015). doi: 10.1016/ j.molcel.2014.12.020; pmid: 25620564
58. J. Son, S. S. Shen, R. Margueron, D. Reinberg, Nucleosomebinding activities within JARID2 and EZH1 regulate the function of PRC2 on chromatin. Genes Dev. 27, 2663-2677 (2013). doi: 10.1101/gad.225888.113; pmid: 24352422
59. R. Cao et al., Role of hPHF1 in H3K27 methylation and Hox gene silencing. Mol. Cell. Biol. 28, 1862-1872 (2008).doi: 10.1128/MCB.01589-07; pmid: 18086877
60. K. Sarma, R. Margueron, A. Ivanov, V. Pirrotta, D. Reinberg, Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Mol. Cell. Biol. 28, 2718-2731 (2008).doi: 10.1128/MCB.02017-07; pmid: 18285464
61. C. A. Musselman et al., Molecular basis for H3K36me3 recognition by the Tudor domain of PHF1. Nat. Struct. Mol. Biol. 19, 1266-1272 (2012). doi: 10.1038/nsmb.2435; pmid: 23142980
62. F. W. Schmitges et al., Histone methylation by PRC2 is inhibited by active chromatin marks. Mol. Cell 42, 330-341 (2011). doi: 10.1016/j.molcel.2011.03.025; pmid: 21549310
63. G. L. Brien et al., Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation. Nat. Struct. Mol. Biol. 19, 1273-1281 (2012). doi: 10.1038/nsmb.2449; pmid: 23160351
64. C. Ballaré et al., Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity. Nat. Struct. Mol. Biol. 19, 1257-1265 (2012). doi: 10.1038/nsmb.2434; pmid: 23104054
65. L. Cai et al., An H3K36 methylation-engaging Tudor motif of polycomb-like proteins mediates PRC2 complex targeting. Mol. Cell 49, 571-582 (2013). doi: 10.1016/ j.molcel.2012.11.026; pmid: 23273982
66. J. A. Simon, R. E. Kingston, Mechanisms of polycomb gene silencing: Knowns and unknowns. Nat. Rev. Mol. Cell Biol. 10, 697-708 (2009). pmid: 19738629
67. P. Vella, I. Barozzi, A. Cuomo, T. Bonaldi, D. Pasini, Yin Yang1 extends the Myc-related transcription factors network in embryonic stem cells. Nucleic Acids Res. 40, 3403-3418 (2012). doi: 10.1093/nar/gkr1290; pmid: 22210892
68. M. Bauer, J. Trupke, L. Ringrose, The quest for mammalian Polycomb response elements: Are we there yet? Chromosoma (2015). doi: 10.1007/s00412-015-0539-4; pmid: 26453572
69. E. M. Mendenhall et al., GC-rich sequence elements recruit PRC2 in mammalian ES cells. PLOS Genet. 6, e1001244 (2010). doi: 10.1371/journal.pgen.1001244; pmid: 21170310
70. P. Jermann, L. Hoerner, L. Burger, D. Schübeler, Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation. Proc. Natl. Acad. Sci. U.S.A. 111, E3415-E3421 (2014). doi: 10.1073/pnas.1400672111; pmid: 25092339
71. E. M. Riising et al., Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide. Mol. Cell 55, 347-360 (2014). doi: 10.1016/ j.molcel.2014.06.005; pmid: 24999238
72. K. H. Hansen et al., A model for transmission of the H3K27me3 epigenetic mark. Nat. Cell Biol. 10, 1291-1300 (2008). doi: 10.1038/ncb1787; pmid: 18931660
73. K. J. Ferrari et al., Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity. Mol. Cell 53, 49-62 (2014). doi: 10.1016/ j.molcel.2013.10.030; pmid: 24289921
74. S. S. Levine 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).doi: 10.1128/MCB.22.17.6070-6078.2002; pmid: 12167701
75. M. D. Gearhart, C. M. Corcoran, J. A. Wamstad, V. J. Bardwell, 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). doi: 10.1128/ MCB.00630-06; pmid: 16943429
76. C. Sánchez 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. Proteomics 6, 820-834 (2007).doi: 10.1074/mcp.M600275-MCP200; pmid: 17296600
77. A. Lagarou et al., dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group silencing. Genes Dev. 22, 2799-2810 (2008). doi: 10.1101/ gad.484208; pmid: 18923078
78. Z. Gao et al., PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes. Mol. Cell 45, 344-356 (2012). doi: 10.1016/j.molcel.2012.01.002; pmid: 22325352
79. H. Wang et al., Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873-878 (2004).doi: 10.1038/nature02985; pmid: 15386022
80. M. Endoh et al., Histone H2A mono-ubiquitination is a crucial step to mediate PRC1-dependent repression of developmental genes to maintain ES cell identity. PLOS Genet. 8, e1002774 (2012). doi: 10.1371/journal. pgen.1002774; pmid: 22844243
81. R. S. Illingworth et al., The E3 ubiquitin ligase activity of RING1B is not essential for early mouse development. Genes Dev. 29, 1897-1902 (2015). pmid: 26385961
82. A. R. Pengelly, R. Kalb, K. Finkl, J. Müller, Transcriptional repression by PRC1 in the absence of H2A monoubiquitylation. Genes Dev. 29, 1487-1492 (2015).doi: 10.1101/gad.265439.115; pmid: 26178786
83. R. Cao, Y. Tsukada, Y. Zhang, Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol. Cell 20, 845-854 (2005). doi: 10.1016/j.molcel.2005.12.002; pmid: 16359901
84. A. Piunti, D. Pasini, Epigenetic factors in cancer development: Polycomb group proteins. Future Oncol. 7, 57-75 (2011).doi: 10.2217/fon.10.157; pmid: 21174538
85. L. Tavares et al., RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell 148, 664-678 (2012).doi: 10.1016/j.cell.2011.12.029; pmid: 22325148
86. L. Morey, L. Aloia, L. Cozzuto, S. A. Benitah, L. Di Croce, RYBP and Cbx7 define specific biological functions of polycomb complexes in mouse embryonic stem cells. Cell Reports 3, 60-69 (2013). doi: 10.1016/ j.celrep.2012.11.026; pmid: 23273917
87. N. P. Blackledge et al., Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell 157, 1445-1459 (2014). doi: 10.1016/ j.cell.2014.05.004; pmid: 24856970
88. R. Kalb et al., Histone H2A monoubiquitination promotes histone H3 methylation in Polycomb repression. Nat. Struct. Mol. Biol. 21, 569-571 (2014). doi: 10.1038/nsmb.2833; pmid: 24837194
89. A. Sparmann, M. van Lohuizen, Polycomb silencers control cell fate, development and cancer. Nat. Rev. Cancer 6, 846-856 (2006). doi: 10.1038/nrc1991; pmid: 17060944
90. V. Orlando, E. P. Jane, V. Chinwalla, P. J. Harte, R. Paro, Binding of trithorax and Polycomb proteins to the bithorax complex: Dynamic changes during early Drosophila embryogenesis. EMBO J. 17, 5141-5150 (1998). doi: 10.1093/ emboj/17.17.5141; pmid: 9724650
91. N. Soshnikova, Dynamics of Polycomb and Trithorax activities during development. Birth Defects Res. A Clin. Mol. Teratol. 91, 781-787 (2011). doi: 10.1002/bdra.20774; pmid: 21290568
92. L. Morey, A. Santanach, L. Di Croce, Pluripotency and epigenetic factors in mouse embryonic stem cell fate regulation. Mol. Cell. Biol. 35, 2716-2728 (2015).doi: 10.1128/MCB.00266-15; pmid: 26031336
93. T. T. Onder et al., Chromatin-modifying enzymes as modulators of reprogramming. Nature 483, 598-602 (2012).doi: 10.1038/nature10953; pmid: 22388813
94. L. A. Boyer et al., Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349-353 (2006). doi: 10.1038/nature04733; pmid: 16625203
95. M. Endoh 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). doi: 10.1242/dev.014340; pmid: 18339675
96. M. Ku et al., Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLOS Genet. 4, e1000242 (2008). doi: 10.1371/ journal.pgen.1000242; pmid: 18974828
97. G. Cavalli, PRC1 proteins orchestrate three-dimensional genome architecture. Nat. Genet. 47, 1105-1106 (2015). doi: 10.1038/ng.3411; pmid: 26417860
98. C. Lanzuolo, V. Roure, J. Dekker, F. Bantignies, V. Orlando, Polycomb response elements mediate the formation of chromosome higher-order structures in the bithorax complex. Nat. Cell Biol. 9, 1167-1174 (2007). doi: 10.1038/ ncb1637; pmid: 17828248
99. F. Bantignies et al., Polycomb-dependent regulatory contacts between distant Hox loci in Drosophila. Cell 144, 214-226 (2011). doi: 10.1016/j.cell.2010.12.026; pmid: 21241892
100. M. Denholtz 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). doi: 10.1016/j.stem.2013.08.013; pmid: 24035354
101. S. Schoenfelder et al., Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome. Nat. Genet. 47, 1179-1186 (2015). doi: 10.1038/ng.3393; pmid: 26323060
102. F. Antequera, A. Bird, Number of CpG islands and genes in human and mouse. Proc. Natl. Acad. Sci. U.S.A. 90, 11995-11999 (1993). doi: 10.1073/pnas.90.24.11995; pmid: 7505451
103. A. Patsialou, D. Wilsker, E. Moran, DNA-binding properties of ARID family proteins. Nucleic Acids Res. 33, 66-80 (2005).doi:10.1093/nar/gki145; pmid: 15640446
104. H. M. Herz et al., Polycomb repressive complex 2-dependent and -independent functions of Jarid2 in transcriptional regulation in Drosophila. Mol. Cell. Biol. 32, 1683-1693 (2012). doi: 10.1128/MCB.06503-11; pmid: 22354997
105. H. K. Long, N. P. Blackledge, R. J. Klose, ZF-CxxC domaincontaining proteins, CpG islands and the chromatin connection. Biochem. Soc. Trans. 41, 727-740 (2013).
106. A. M. Farcas et al., KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands. eLife 1, e00205 (2012). doi: 10.7554/eLife.00205; pmid: 23256043
107. J. He 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).doi: 10.1038/ncb2702; pmid: 23502314
108. X. Wu, J. V. Johansen, K. Helin, Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Mol. Cell 49, 1134-1146 (2013).doi: 10.1016/j.molcel.2013.01.016; pmid: 23395003
109. L. Morey et al., Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells. Cell Stem Cell 10, 47-62 (2012). doi: 10.1016/ j.stem.2011.12.006; pmid: 22226355
110. A. O'Loghlen et al., MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation. Cell Stem Cell 10, 33-46 (2012). doi: 10.1016/ j.stem.2011.12.004; pmid: 22226354
111. B. E. Bernstein et al., A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315-326 (2006). doi: 10.1016/j.cell.2006.02.041; pmid: 16630819
112. K. Cui et al., Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell 4, 80-93 (2009).doi: 10.1016/j.stem.2008.11.011; pmid: 19128795
113. T. S. Mikkelsen et al., Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553-560 (2007). doi: 10.1038/nature06008; pmid: 17603471
114. N. S. Christophersen, K. Helin, Epigenetic control of embryonic stem cell fate. J. Exp. Med. 207, 2287-2295 (2010). doi: 10.1084/jem.20101438; pmid: 20975044
115. P. Voigt, W. W. Tee, D. Reinberg, A double take on bivalent promoters. Genes Dev. 27, 1318-1338 (2013). doi: 10.1101/ gad.219626.113; pmid: 23788621;
116. S. Lubitz, S. Glaser, J. Schaft, A. F. Stewart, K. Anastassiadis, Increased apoptosis and skewed differentiation in mouse embryonic stem cells lacking the histone methyltransferase Mll2. Mol. Biol. Cell 18, 2356-2366 (2007). doi: 10.1091/mbc. E06-11-1060; pmid: 17429066
117. A. S. Bledau et al., The H3K4 methyltransferase Setd1a is first required at the epiblast stage, whereas Setd1b becomesessential after gastrulation. Development 141, 1022-1035 (2014). doi: 10.1242/dev.098152; pmid: 24550110
118. M. A. Morgan, A. Shilatifard, Chromatin signatures of cancer. Genes Dev. 29, 238-249 (2015). doi: 10.1101/gad.255182.114; pmid: 25644600
119. M. Mohan, C. Lin, E. Guest, A. Shilatifard, Licensed to elongate: A molecular mechanism for MLL-based leukaemogenesis. Nat. Rev. Cancer 10, 721-728 (2010).doi: 10.1038/nrc2915; pmid: 20844554
120. J. J. Schuringa, E. Vellenga, Role of the polycomb group gene BMI1 in normal and leukemic hematopoietic stem and progenitor cells. Curr. Opin. Hematol. 17, 294-299 (2010).doi: 10.1097/MOH.0b013e328338c439; pmid: 20308890
121. K. A. Skulte, L. Phan, S. J. Clark, P. C. Taberlay, Chromatin remodeler mutations in human cancers: Epigenetic implications. Epigenomics 6, 397-414 (2014). doi: 10.2217/ epi.14.37; pmid: 25333849
122. W. Timp, A. P. Feinberg, Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat. Rev. Cancer 13, 497-510 (2013). doi: 10.1038/ nrc3486; pmid: 23760024
123. G. Cimino et al., Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13) chromosome translocations. Cancer Res. 51, 6712-6714 (1991). pmid: 1835902
124. T. Cierpicki et al., Structure of the MLL CXXC domain-DNA complex and its functional role in MLL-AF9 leukemia. Nat. Struct. Mol. Biol. 17, 62-68 (2010). doi: 10.1038/nsmb.1714; pmid: 20010842
125. P. M. Ayton, E. H. Chen, M. L. Cleary, Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein. Mol. Cell. Biol. 24, 10470-10478 (2004).doi: 10.1128/MCB.24.23.10470-10478.2004; pmid: 15542854
126. A. Shilatifard, W. S. Lane, K. W. Jackson, R. C. Conaway, J. W. Conaway, An RNA polymerase II elongation factor encoded by the human ELL gene. Science 271, 1873-1876 (1996). doi: 10.1126/science.271.5257.1873; pmid: 8596958
127. J. E. Rubnitz, J. Morrissey, P. A. Savage, M. L. Cleary, ENL, the gene fused with HRX in t(11;19) leukemias, encodes a nuclear protein with transcriptional activation potential in lymphoid and myeloid cells. Blood 84, 1747-1752 (1994).pmid: 8080983
128. R. Prasad et al., Domains with transcriptional regulatory activity within the ALL1 and AF4 proteins involved in acute leukemia. Proc. Natl. Acad. Sci. U.S.A. 92, 12160-12164 (1995). doi: 10.1073/pnas.92.26.12160; pmid: 8618864
129. C. Lin et al., AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol. Cell 37, 429-437 (2010). doi: 10.1016/j.molcel.2010.01.026; pmid: 20159561
130. A. Yokoyama, M. Lin, A. Naresh, I. Kitabayashi, M. L. Cleary, A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLLdependent transcription. Cancer Cell 17, 198-212 (2010). doi: 10.1016/j.ccr.2009.12.040; pmid: 20153263
131. Y. X. Chen et al., The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression. Proc. Natl. Acad. Sci. U.S.A. 103, 1018-1023 (2006). doi: 10.1073/pnas.0510347103; pmid: 16415155
132. A. T. Thiel et al., MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 17, 148-159 (2010). doi: 10.1016/j.ccr.2009.12.034; pmid: 20159607
133. F. Cao et al., Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol. Cell 53, 247-261 (2014). doi: 10.1016/j.molcel.2013.12.001; pmid: 24389101
134. F. Grebien et al., Pharmacological targeting of the Wdr5-MLL interaction in C/EBPa N-terminal leukemia. Nat. Chem. Biol. 11, 571-578 (2015). doi: 10.1038/nchembio.1859; pmid: 26167872
135. M. A. Dawson, T. Kouzarides, Cancer epigenetics: From mechanism to therapy. Cell 150, 12-27 (2012). doi: 10.1016/ j.cell.2012.06.013; pmid: 22770212
136. S. B. Ng et al., Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 42, 790-793 (2010). doi: 10.1038/ng.646; pmid: 20711175
137. L. Pasqualucci et al., Analysis of the coding genome of diffuse large B-cell lymphoma. Nat. Genet. 43, 830-837 (2011).doi: 10.1038/ng.892; pmid: 21804550
138. R. D. Morin et al., Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298-303 (2011). doi: 10.1038/nature10351; pmid: 21796119
139. J. Zhang et al., Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat. Med. 21, 1190-1198 (2015). doi: 10.1038/nm.3940; pmid: 26366712
140. A. Ortega-Molina et al., The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat. Med. 21, 1199-1208 (2015). doi: 10.1038/nm.3943; pmid: 26366710
141. D. W. Parsons et al., The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435-439 (2011).doi: 10.1126/science.1198056; pmid: 21163964
142. C. Kandoth et al., Mutational landscape and significance across 12 major cancer types. Nature 502, 333-339 (2013).doi: 10.1038/nature12634; pmid: 24132290
143. Y. Gui et al., Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43, 875-878 (2011). doi: 10.1038/ng.907; pmid: 21822268
144. G. Guo et al., Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat. Genet. 45, 1459-1463 (2013). doi: 10.1038/ng.2798; pmid: 24121792
145. J. Lee et al., A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4. Proc. Natl. Acad. Sci. U.S.A. 106, 8513-8518 (2009). doi: 10.1073/pnas.0902873106; pmid: 19433796
146. G. van Haaften et al., Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521-523 (2009). doi: 10.1038/ng.349; pmid: 19330029
147. J. Van der Meulen et al., The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. Blood 125, 13-21 (2015).doi: 10.1182/blood-2014-05-577270; pmid: 25320243
148. P. Ntziachristos et al., Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514, 513-517 (2014). doi: 10.1038/nature13605; pmid: 25132549
149. K. Agger et al., UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449, 731-734 (2007). doi: 10.1038/ nature06145; pmid: 17713478
150. E. Calo, J. Wysocka, Modification of enhancer chromatin: What, how, and why? Mol. Cell 49, 825-837 (2013).doi: 10.1016/j.molcel.2013.01.038; pmid: 23473601
151. B. Akhtar-Zaidi et al., Epigenomic enhancer profiling defines a signature of colon cancer. Science 336, 736-739 (2012).doi: 10.1126/science.1217277; pmid: 22499810
152. S. Varambally et al., The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624-629 (2002). doi: 10.1038/nature01075; pmid: 12374981
153. A. P. Bracken et al., EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323-5335 (2003). doi: 10.1093/emboj/ cdg542; pmid: 14532106
154. A. Piunti et al., Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication. Nat. Commun. 5, 3649 (2014).doi: 10.1038/ncomms4649; pmid: 24728135
155. R. D. Morin et al., Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinalcenter origin. Nat. Genet. 42, 181-185 (2010). doi: 10.1038/ ng.518; pmid: 20081860
156. F. J. van Kemenade et al., Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma. Blood 97, 3896-3901 (2001). doi: 10.1182/blood.V97.12.3896; pmid: 11389032
157. C. J. Sneeringer et al., Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl. Acad. Sci. U.S.A. 107, 20980-20985 (2010).doi: 10.1073/pnas.1012525107; pmid: 21078963
158. D. B. Yap et al., Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451-2459 (2011). doi: 10.1182/blood-2010-11-321208; pmid: 21190999
159. S. K. Knutson et al., A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890-896 (2012). pmid: 23023262
160. M. T. McCabe et al., EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108-112 (2012). doi: 10.1038/nature11606; pmid: 23051747
161. W. Béguelin et al., EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677-692 (2013).doi: 10.1016/j.ccr.2013.04.011; pmid: 23680150
162. C. Simon et al., A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev. 26, 651-656 (2012). doi: 10.1101/gad.186411.111; pmid: 22431509
163. P. Ntziachristos et al., Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat. Med. 18, 298-303 (2012). doi: 10.1038/nm.2651; pmid: 22237151
164. M. Mochizuki-Kashio et al., Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. Blood 126, 1172-1183 (2015). doi: 10.1182/blood-2015-03-634428; pmid: 26219303
165. W. Lee et al., PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat. Genet. 46, 1227-1232 (2014). doi: 10.1038/ng.3095; pmid: 25240281
166. M. Zhang et al., Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat. Genet. 46, 1170-1172 (2014). doi: 10.1038/ng.3116; pmid: 25305755
167. G. Wu et al.St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project, Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251-253 (2012). doi: 10.1038/ng.1102; pmid: 22286216
168. J. Schwartzentruber et al., Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226-231 (2012). doi: 10.1038/nature10833; pmid: 22286061
169. P. W. Lewis et al., Inhibition of PRC2 activity by a gain-offunction H3 mutation found in pediatric glioblastoma. Science 340, 857-861 (2013). doi: 10.1126/science.1232245; pmid: 23539183
170. K. M. Chan et al., The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 27, 985-990 (2013). doi: 10.1101/gad.217778.113; pmid: 23603901
171. S. Bender et al., Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24, 660-672 (2013). doi: 10.1016/j.ccr.2013.10.006; pmid: 24183680
172. H. M. Herz et al., Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling. Science 345, 1065-1070 (2014). doi: 10.1126/science.1255104; pmid: 25170156
173. M. Jung, K. A. Gelato, A. Fernández-Montalván, S. Siegel, B. Haendler, Targeting BET bromodomains for cancer treatment. Epigenomics 7, 487-501 (2015). doi: 10.2217/epi.14.91; pmid: 26077433
174. T. De Raedt et al., PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514, 247-251 (2014). pmid: 25119042
175. D. Pasini 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).doi: 10.1093/nar/gkq244; pmid: 20385584
176. K. Funato, T. Major, P. W. Lewis, C. D. Allis, V. Tabar, Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science 346, 1529-1533 (2014).doi: 10.1126/science.1253799; pmid: 25525250
177. R. Hashizume et al., Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20, 1394-1396 (2014). pmid: 25401693
178. S. Henikoff, A. Shilatifard, Histone modification: Cause or cog? Trends Genet. 27, 389-396 (2011). doi: 10.1016/ j.tig.2011.06.006; pmid: 21764166
179. A. R. Pengelly, Ö. Copur, H. Jäckle, A. Herzig, J. Müller, A histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. Science 339, 698-699 (2013). doi: 10.1126/science.1231382; pmid: 23393264
180. R. Eskeland et al., Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination. Mol. Cell 38, 452-464 (2010). doi: 10.1016/ j.molcel.2010.02.032; pmid: 20471950
181. N. J. Francis, R. E. Kingston, C. L. Woodcock, Chromatin compaction by a polycomb group protein complex. Science 306, 1574-1577 (2004). doi: 10.1126/science.1100576; pmid: 15567868
182. K. Xu et al., EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 338, 1465-1469 (2012). pmid: 23239736
183. C. Kadoch, G. R. Crabtree, Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci. Adv. 1, e1500447 (2015).doi: 10.1126/sciadv.1500447; pmid: 26601204
184. T. Li et al., SET1A cooperates with CUDR to promote liver cancer growth and hepatocyte-like stem cell malignant transformation epigenetically. Mol. Ther. 24, 261-275 (2016). doi: 10.1038/mt.2015.208; pmid: 26581161
185. B. D. Yu, J. L. Hess, S. E. Horning, G. A. Brown, S. J. Korsmeyer, Altered Hox expression and segmental identity in Mll-mutant mice. Nature 378, 505-508 (1995).doi: 10.1038/378505a0; pmid: 7477409
186. S. Glaser et al., The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis. Epigenetics Chromatin 2, 5 (2009).doi: 10.1186/1756-8935-2-5; pmid: 19348672
187. J. E. Lee et al., H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). doi: 10.7554/eLife.01503; pmid: 24368734
188. J. Z. Stoller et al., Ash2l interacts with Tbx1 and is required during early embryogenesis. Exp. Biol. Med. (Maywood) 235, 569-576 (2010). doi: 10.1258/ebm.2010.009318; pmid: 20463296
189. J. Qi, L. Huo, Y. T. Zhu, Y. J. Zhu, Absent, small or homeotic 2-like protein (ASH2L) enhances the transcription of the estrogen receptor a gene through GATA-binding protein 3 (GATA3). J. Biol. Chem. 289, 31373-31381 (2014).doi: 10.1074/jbc.M114.579839; pmid: 25258321
190. A. Bertero et al., Activin/nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark. Genes Dev. 29, 702-717 (2015). doi: 10.1101/gad.255984.114; pmid: 25805847
191. J. S. Crabtree et al., A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc. Natl. Acad. Sci. U.S.A. 98, 1118-1123 (2001). doi: 10.1073/ pnas.98.3.1118; pmid: 11158604
192. S. C. Chandrasekharappa et al., Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276, 404-407 (1997). doi: 10.1126/science.276.5311.404; pmid: 9103196
193. J. Grembecka et al., Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 8, 277-284 (2012). doi: 10.1038/nchembio.773; pmid: 22286128
194. D. Borkin et al., Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell 27, 589-602 (2015). doi: 10.1016/ j.ccell.2015.02.016; pmid: 25817203
195. S. Minocha, T.-L. Sung, D. Villeneuve, F. Lammers, W. Herr, Compensatory embryonic response to allele-specific inactivation of the murine X-linked gene Hcfc1. Dev. Biol. 412, 1-17 (2016). doi: 10.1016/j.ydbio.2016.02.019; pmid: 26921005
196. E. A. Cho, M. J. Prindle, G. R. Dressler, BRCT domaincontaining protein PTIP is essential for progression through mitosis. Mol. Cell. Biol. 23, 1666-1673 (2003). doi: 10.1128/MCB.23.5.1666-1673.2003; pmid: 12588986
197. E. Callen et al., 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 153, 1266-1280 (2013). doi: 10.1016/j.cell.2013.05.023; pmid: 23727112
198. C. Wang et al., UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proc. Natl. Acad. Sci. U.S.A. 109, 15324-15329 (2012). doi: 10.1073/pnas.1204166109; pmid: 22949634
199. J. H. Kim et al., UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells. Cancer Res. 74, 1705-1717 (2014). doi: 10.1158/0008-5472.CAN-13-1896; pmid: 24491801
200. M. A. Mahajan, H. H. Samuels, Nuclear receptor coactivator/ coregulator NCoA6(NRC) is a pleiotropic coregulator involved in transcription, cell survival, growth and development. Nucl. Recept. Signal. 6, e002 (2008). pmid: 18301782
201. D. O'Carroll et al., The polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330-4336 (2001). doi: 10.1128/MCB.21.13.4330-4336.2001; pmid: 11390661
202. K. H. Kim, C. W. Roberts, Targeting EZH2 in cancer. Nat. Med. 22, 128-134 (2016). doi: 10.1038/nm.4036; pmid: 26845405
203. K. H. Kim et al., SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491-1496 (2015). doi: 10.1038/nm.3968; pmid: 26552009
204. B. G. Bitler et al., Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat. Med. 21, 231-238 (2015). pmid: 25686104
205. L. M. LaFave et al., Loss of BAP1 function leads to EZH2-dependent transformation. Nat. Med. 21, 1344-1349 (2015).doi: 10.1038/nm.3947; pmid: 26437366
206. R. Bejar et al., Clinical effect of point mutations in myelodysplastic syndromes. N. Engl. J. Med. 364, 2496-2506 (2011). doi: 10.1056/NEJMoa1013343; pmid: 21714648
207. E. Ezhkova et al., EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev. 25, 485-498 (2011). doi: 10.1101/gad.2019811; pmid: 21317239
208. J. I. Koontz et al., Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc.Natl.Acad.Sci.U.S.A. 98, 6348-6353 (2001). doi: 10.1073/pnas.101132598; pmid: 11371647
209. A. Schumacher, C. Faust, T. Magnuson, Positional cloning of a global regulator of anterior-posterior patterning in mice. Nature 384, 648 (1996). doi: 10.1038/384648a0; pmid: 8984348
210. T. Neff et al., Polycomb repressive complex 2 is required for MLL-AF9 leukemia. Proc. Natl. Acad. Sci. U.S.A. 109, 5028-5033 (2012). doi: 10.1073/pnas.1202258109; pmid: 22396593
211. W. Kim et al., Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat. Chem. Biol. 9, 643-650 (2013). doi: 10.1038/nchembio.1331; pmid: 23974116
212. M. Serresi et al., Polycomb repressive complex 2 is a barrier to KRAS-driven inflammation and epithelial-mesenchymal transition in non-small-cell lung cancer. Cancer Cell 29, 17-31 (2016). doi: 10.1016/j.ccell.2015.12.006; pmid: 26766588
213. H. H. Yeh et al., Ras induces experimental lung metastasis through up-regulation of RbAp46 to suppress RECK promoter activity. BMC Cancer 15, 172 (2015). doi: 10.1186/ s12885-015-1155-7; pmid: 25885317
214. T. Takeuchi, M. Kojima, K. Nakajima, S. Kondo, jumonji gene is essential for the neurulation and cardiac development of mouse embryos with a C3H/He background. Mech. Dev. 86, 29-38 (1999). doi: 10.1016/S0925-4773(99)00100-8; pmid: 10446263
215. Z. S. Walters et al., JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells. Oncogene 33, 1148-1157 (2014).doi: 10.1038/onc.2013.46; pmid: 23435416
216. J. W. Voncken et al., Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc. Natl. Acad.Sci. U.S.A. 100, 2468-2473 (2003). doi: 10.1073/ pnas.0434312100; pmid: 12589020
217. K. Rai et al., Dual Roles of RNF2 in Melanoma Progression. Cancer Discov. 5, 1314-1327 (2015). doi: 10.1158/2159-8290.CD-15-0493; pmid: 26450788
218. V. van den Boom et al., Non-canonical PRC1.1 targets active genes independent of H3K27me3 and Is Essential for Leukemogenesis. Cell Reports 14, 332-346 (2016).doi: 10.1016/j.celrep.2015.12.034; pmid: 26748712
219. M. del Mar Lorente et al., Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice. Development 127, 5093-5100 (2000). pmid: 11060235
220. N. M. van der Lugt et al., Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757-769 (1994). doi: 10.1101/gad.8.7.757; pmid: 7926765
221. Y. Haupt, M. L. Bath, A. W. Harris, J. M. Adams, bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis. Oncogene 8, 3161-3164 (1993).pmid: 8414519
222. J. J. Jacobs et al., Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13, 2678-2690 (1999). doi: 10.1101/ gad.13.20.2678; pmid: 10541554
223. J. Lessard, G. Sauvageau, Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255-260 (2003). doi: 10.1038/nature01572; pmid: 12714970
224. S. W. Bruggeman et al., Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12, 328-341 (2007). doi: 10.1016/ j.ccr.2007.08.032; pmid: 17936558
225. H. Oguro et al., Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes. J. Exp. Med. 209, 445-454 (2012). doi: 10.1084/jem.20111709; pmid: 22351929
226. T. Akasaka et al., A role for mel-18, a Polycomb group-related vertebrate gene, during theanteroposterior specification of the axial skeleton. Development 122, 1513-1522 (1996).pmid: 8625838
227. W. J. Guo et al., Mel-18 acts as a tumor suppressor by repressing Bmi-1 expression and down-regulating Akt activity in breast cancer cells. Cancer Res. 67, 5083-5089 (2007).doi: 10.1158/0008-5472.CAN-06-4368; pmid: 17545584
228. J. Y. Lee et al., Mel-18 negatively regulates INK4a/ARFindependent cell cycle progression via Akt inactivation in breast cancer. Cancer Res. 68, 4201-4209 (2008). doi: 10.1158/0008-5472.CAN-07-2570; pmid: 18519679
229. N. Coré et al., Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development 124, 721-729 (1997). pmid: 9043087
230. Y. Katoh-Fukui et al., Male-to-female sex reversal in M33 mutant mice. Nature 393, 688-692 (1998). doi: 10.1038/ 31482; pmid: 9641679
231. B. Liu et al., Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. Development 140, 780-788 (2013). doi: 10.1242/dev.085035; pmid: 23362346
232. J. Li et al., Cbx4 governs HIF-1a to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity.Cancer Cell 25, 118-131 (2014). doi: 10.1016/ j.ccr.2013.12.008; pmid: 24434214
233. F. Forzati et al., CBX7 is a tumor suppressor in mice and humans. J. Clin. Invest. 122, 612-623 (2012). doi: 10.1172/ JCI58620; pmid: 22214847
234. F. Forzati et al., CBX7 gene expression plays a negative role in adipocyte cell growth and differentiation. Biol. Open 3, 871-879 (2014). doi: 10.1242/bio.20147872; pmid: 25190058
235. C. L. Scott et al., Role of the chromobox protein CBX7 in lymphomagenesis. Proc. Natl. Acad. Sci. U.S.A. 104, 5389-5394 (2007). doi: 10.1073/pnas.0608721104; pmid: 17374722
236. K. Klauke et al., Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat. Cell Biol. 15, 353-362 (2013).doi: 10.1038/ncb2701; pmid: 23502315
237. J. Tan et al., CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell 20, 563-575 (2011). doi: 10.1016/j.ccr.2011.09.008; pmid: 22094252
238. Y. Takihara et al., Targeted disruption of the mouse homologue of the Drosophila polyhomeotic gene leads to altered anteroposterior patterning and neural crest defects. Development 124, 3673-3682 (1997). pmid: 9367423
239. K. Isono et al., Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes. Mol. Cell. Biol. 25, 6694-6706 (2005).doi: 10.1128/MCB.25.15.6694-6706.2005; pmid: 16024804
240. M. K. Pirity, J. Locker, N. Schreiber-Agus, Rybp/DEDAF is required for early postimplantation and for central nervous system development. Mol. Cell. Biol. 25, 7193-7202 (2005).doi: 10.1128/MCB.25.16.7193-7202.2005; pmid: 16055728
241. A. A. Danen-van Oorschot et al., Human death effector domain-associated factor interacts with the viral apoptosis agonist Apoptin and exerts tumor-preferential cell killing. Cell Death Differ. 11, 564-573 (2004). doi: 10.1038/ sj.cdd.4401391; pmid: 14765135
242. J. Andricovich, Y. Kai, W. Peng, A. Foudi, A. Tzatsos, Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis. J. Clin. Invest. 126, 905-920 (2016). doi: 10.1172/JCI84014; pmid: 26808549
243. A. Tzatsos et al., KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J. Clin. Invest. 123, 727-739 (2013).pmid: 23321669