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  • Review Article
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Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers

Nature Reviews Cancer volume 10, pages 457–469 (2010)Cite this article

Subjects

Key Points

  • Post-translational modifications of histones introduce meaningful variations into chromatin and provide a regulatory platform for controlling and/or fine-tuning many important DNA-templated processes, including gene transcription, the repair of DNA damage and DNA replication.

  • Histone modifications, together with factors responsible for adding ('writing'), interpreting ('reading') and removing ('erasing') histone modifications, regulate specific and distinct functional outputs of our genomes, which constitute the basis of the 'histone code hypothesis'.

  • As recent evidence starts to link the miswriting, misinterpretation and mis-erasing of histone modifications to oncogenesis, we further propose that misregulation of the histone code leads to deregulated gene expression and perturbation of cellular identity, and is therefore a major contributor to cancer initiation, progression and/or metastasis.

  • Mixed lineage leukaemia (MLL) and enhancer of zeste 2 (EZH2) catalyse the addition of methylation of histone H3 lysine 4 (H3K4) and H3 lysine 27 (H3K27), respectively, which are arguably two of the most important histone methylation marks. MLL rearrangement and deregulation of EZH2 are among the most common mutations in leukaemia and solid tumours, respectively.

  • Several plant homoedomain (PHD) finger-containing proteins have recently been identified as reading factors of trimethylation of H3K4 (H3K4me3). Misinterpretation of H3K4me3 by leukaemia-associated translocations of PHD finger factors (NUP98–JARID1A or NUP98–PHF23) is crucial for the induction of myeloid leukaemia; somatic mutations of ING1, a PHD finger factor, interfere with the reading of H3K4me3 and associate with the development of oesophageal squamous cell carcinoma, head and neck squamous cell carcinoma and melanoma.

  • Deregulation or mutations of the recently identified H3K4- or H3K27-specific histone demethylases have been observed in solid tumours. However, their involvement in cancer development and underlying mechanisms are largely unclear.

Abstract

Post-translational modification of histones provides an important regulatory platform for processes such as gene transcription and DNA damage repair. It has become increasingly apparent that the misregulation of histone modification, which is caused by the deregulation of factors that mediate the modification installation, removal and/or interpretation, actively contributes to human cancer. In this Review, we summarize recent advances in understanding the interpretation of certain histone methylations by plant homeodomain finger-containing proteins, and how misreading, miswriting and mis-erasing of histone methylation marks can be associated with oncogenesis and progression. These observations provide us with a greater mechanistic understanding of epigenetic alterations in human cancers and might also help direct new therapeutic interventions in the future.

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Figure 1: Miswriting of histone methylation is associated with cancer initiation and/or progression.
Figure 2: Reading or mis-reading the H3K4me3 marks by PHD finger-containing factors in normal cellular processes and during cancer development.
Figure 3: Mis-erasing of histone methylation is associated with cancer development.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001). In references 1 and 2, the authors first proposed the histone code hypothesis that is currently under active investigation.

    Article  CAS  PubMed  Google Scholar 

  3. Wang, G. G., Allis, C. D. & Chi, P. Chromatin remodeling and cancer, Part I: covalent histone modifications. Trends Mol. Med. 13, 363–372 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ruthenburg, A. J., Allis, C. D. & Wysocka, J. Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol. Cell 25, 15–30 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Klose, R. J. & Zhang, Y. Regulation of histone methylation by demethylimination and demethylation. Nature Rev. Mol. Cell Biol. 8, 307–318 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Feinberg, A. P., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nature Rev. Genet. 7, 21–33 (2006). The authors propose the epigenetic progenitor origin model of oncogenesis, in which cancer first arises from polyclonal epigenetic disruption of stem and progenitor cells.

    Article  CAS  PubMed  Google Scholar 

  11. Seligson, D. B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391–400 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Shi, X. et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li, H. et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91–95 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pena, P. V. et al. Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442, 100–103 (2006). References 13–16 are the landmark papers that first described PHD finger motifs as readers or effectors of H3K4me3. Reference 14 also unveils the role of the ING2 tumour suppressor and the reading of H3K4me3 in efficient DNA damage-induced responses aiming to decelerate cell cycle progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Baker, L. A., Allis, C. D. & Wang, G. G. PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. Mutat. Res. 647, 3–12 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. van Ingen, H. et al. Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit TAF3. Structure 16, 1245–1256 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Matthews, A. G. et al. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J. recombination. Nature 450, 1106–1110 (2007). The first report that links the misreading of histone modification to human disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang, G. G. et al. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459, 847–851 (2009). The first report that links misregulation in functional readout of histone modification to human cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Huang, J. et al. p53 is regulated by the lysine demethylase LSD1. Nature 449, 105–108 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Lan, F. & Shi, Y. Epigenetic regulation: methylation of histone and non-histone proteins. Sci. China C. Life Sci. 52, 311–322 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Sims, R. J., 3rd & Reinberg, D. Is there a code embedded in proteins that is based on post-translational modifications? Nature Rev. Mol. Cell Biol. 9, 815–820 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modifications and leukaemia stem-cell development. Nature Rev. Cancer 7, 823–833 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Yokoyama, A. & Cleary, M. L. Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell 14, 36–46 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hess, J. L. MLL: a histone methyltransferase disrupted in leukemia. Trends Mol. Med. 10, 500–507 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Shih, L. Y. et al. Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement. Leukemia 20, 218–223 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Dorrance, A. M. et al. The Mll partial tandem duplication: differential, tissue-specific activity in the presence or absence of the wild-type allele. Blood 112, 2508–2511 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dorrance, A. M. et al. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J. Clin. Invest. 116, 2707–2716 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kroon, E. et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 17, 3714–3725 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Argiropoulos, B. & Humphries, R. K. Hox genes in hematopoiesis and leukemogenesis. Oncogene 26, 6766–6776 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Slany, R. K. The molecular biology of mixed lineage leukemia. Haematologica 94, 984–993 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–78 (2005). The first report that links MLL fusions to DOT1L, a histone H3K79 methyltransferase, in leukaemia.

    Article  CAS  PubMed  Google Scholar 

  40. Okada, Y. et al. Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L. Nature Cell Biol. 8, 1017–1024 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Mueller, D. et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood 110, 4445–4454 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Milne, T. A., Martin, M. E., Brock, H. W., Slany, R. K. & Hess, J. L. Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. Cancer Res. 65, 11367–11374 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Krivtsov, A. V. et al. H3K79 methylation profiles define murine and human MLL–AF4 leukemias. Cancer Cell 14, 355–368 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Guenther, M. G. et al. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. Genes Dev. 22, 3403–3408 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Thiel, A. T. et al. MLL–AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 17, 148–159 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Steger, D. J. et al. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Mol. Cell. Biol. 28, 2825–2839 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schulze, J. M. et al. Linking cell cycle to histone modifications: SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation. Mol. Cell 35, 626–641 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mellor, J. Linking the cell cycle to histone modifications: Dot1, G1/S, and cycling K79me2. Mol. Cell 35, 729–730 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Mohan, M. et al. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev. 24, 574–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bitoun, E., Oliver, P. L. & Davies, K. E. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum. Mol. Genet. 16, 92–106 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Park, G., Gong, Z., Chen, J. & Kim, J. E. Characterization of the DOT1L network: implications of diverse roles for DOT1L. Protein J. 29, 213–223 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Zhang, W., Xia, X., Reisenauer, M. R., Hemenway, C. S. & Kone, B. C. Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCα in an aldosterone-sensitive manner. J. Biol. Chem. 281, 18059–18068 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Lin, C. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mueller, D. et al. Misguided transcriptional elongation causes mixed lineage leukemia. PLoS Biol. 7, e1000249 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Cheung, N., Chan, L. C., Thompson, A., Cleary, M. L. & So, C. W. Protein arginine-methyltransferase-dependent oncogenesis. Nature Cell Biol. 9, 1208–1215 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Simon, J. A. & Lange, C. A. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res. 647, 21–29 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Bracken, A. P. & Helin, K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nature Rev. Cancer 9, 773–784 (2009).

    Article  CAS  Google Scholar 

  58. Gonzalez, M. E. et al. Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1. Oncogene 28, 843–853 (2009).

    Article  PubMed  CAS  Google Scholar 

  59. Yu, J. et al. Integrative genomics analysis reveals silencing of β-adrenergic signaling by polycomb in prostate cancer. Cancer Cell 12, 419–431 (2007). A comprehensive study of EZH2 and its role in the promotion of prostate cancer by using in vitro cell and xenograft tumour models, and genomic approaches.

    Article  CAS  PubMed  Google Scholar 

  60. Cao, Q. et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27, 7274–7284 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fujii, S. & Ochiai, A. Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells. Cancer Sci. 99, 738–746 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Yang, X. et al. CDKN1C (p57) is a direct target of EZH2 and suppressed by multiple epigenetic mechanisms in breast cancer cells. PLoS ONE 4, e5011 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Ougolkov, A. V., Bilim, V. N. & Billadeau, D. D. Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin. Cancer Res. 14, 6790–6796 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature Genet. 42, 181–185.

  66. Fiskus, W. et al. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 114, 2733–2743 (2009). A study showing an early success of the combined use of the EZH2 inhibitor and HDAC inhibitors in the treatment of leukaemia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Xu, S. & Powers, M. A. Nuclear pore proteins and cancer. Semin. Cell Dev. Biol. 20, 620–630 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cui, K. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sykes, D. B. & Kamps, M. P. E2a/Pbx1 induces the rapid proliferation of stem cell factor-dependent murine pro-T cells that cause acute T-lymphoid or myeloid leukemias in mice. Mol. Cell. Biol. 24, 1256–1269 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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. 12 April 2010 [epub ahead of print].

  71. Coles, A. H. & Jones, S. N. The ING gene family in the regulation of cell growth and tumorigenesis. J. Cell. Physiol. 218, 45–57 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ythier, D., Larrieu, D., Brambilla, C., Brambilla, E. & Pedeux, R. The new tumor suppressor genes ING: genomic structure and status in cancer. Int. J. Cancer 123, 1483–1490 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Soliman, M. A. & Riabowol, K. After a decade of study-ING, a PHD for a versatile family of proteins. Trends Biochem. Sci. 32, 509–519 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Shah, S., Smith, H., Feng, X., Rancourt, D. E. & Riabowol, K. ING function in apoptosis in diverse model systems. Biochem. Cell Biol. 87, 117–125 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Pena, P. V. et al. Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor. J. Mol. Biol. 380, 303–312 (2008). A structural study to demonstrate that cancer-associated somatic mutations of ING1 interfere with its H3K4me3-reading activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Saksouk, N. et al. HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail. Mol. Cell 33, 257–265 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hung, T. et al. ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation. Mol. Cell 33, 248–256 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Doyon, Y. et al. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol. Cell 21, 51–64 (2006). References 77 and 78 demonstrate that a putative tumour suppressor ING4 coordinates the reading of H3K4me3 to subsequent events of chromatin modulation and events related to regulation of cell growth and apoptosis.

    Article  CAS  PubMed  Google Scholar 

  79. Coles, A. H. et al. p37Ing1b regulates B-cell proliferation and cooperates with p53 to suppress diffuse large B-cell lymphomagenesis. Cancer Res. 68, 8705–8714 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Shiseki, M. et al. p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res. 63, 2373–2378 (2003).

    CAS  PubMed  Google Scholar 

  81. Garkavtsev, I. et al. The candidate tumour suppressor p33ING1 cooperates with p53 in cell growth control. Nature 391, 295–298 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Garkavtsev, I., Kazarov, A., Gudkov, A. & Riabowol, K. Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation. Nature Genet. 14, 415–420 (1996). References 81 and 82 are initial reports that describe the tumour suppressive activity of ING family proteins.

    Article  CAS  PubMed  Google Scholar 

  83. Jones, D. R. et al. Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kβ. Mol. Cell 23, 685–695 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Huang, W. et al. Stabilized phosphatidylinositol-5-phosphate analogues as ligands for the nuclear protein ING2: chemistry, biology, and molecular modeling. J. Am. Chem. Soc. 129, 6498–6506 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chan, D. A. et al. Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell 15, 527–538 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Jennes, I. et al. Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum. Mutat. 30, 1620–1627 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Klaus, A. & Birchmeier, W. Wnt signalling and its impact on development and cancer. Nature Rev. Cancer 8, 387–398 (2008).

    Article  CAS  Google Scholar 

  88. Kramps, T. et al. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell 109, 47–60 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Fiedler, M. et al. Decoding of methylated histone H3 tail by the Pygo–BCL9 Wnt signaling complex. Mol. Cell 30, 507–518 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gu, B. et al. Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation. J. Cell Biol. 185, 811–826 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Andrews, P. G., Lake, B. B., Popadiuk, C. & Kao, K. R. Requirement of Pygopus 2 in breast cancer. Int. J. Oncol. 30, 357–363 (2007).

    CAS  PubMed  Google Scholar 

  92. Kessler, R., Hausmann, G. & Basler, K. The PHD domain is required to link Drosophila Pygopus to Legless/β-catenin and not to histone H3. Mech. Dev. 126, 752–759 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  94. Wang, Y. et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138, 660–672 (2009). A comprehensive study of LSD1, a histone H3K4me2/1 demethylase, and its role in the inhibition of the metastasis in breast cancers.

    Article  CAS  PubMed  Google Scholar 

  95. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Yamane, K. et al. PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Mol. Cell 25, 801–812 (2007). A study describing the functions of PLU1 in H3K4me3/2 demethylation and the promotion of breast cancer development.

    Article  CAS  PubMed  Google Scholar 

  97. Xiang, Y. et al. JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer. Proc. Natl Acad. Sci. USA 104, 19226–19231 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Scibetta, A. G. et al. Functional analysis of the transcription repressor PLU-1/JARID1B. Mol. Cell. Biol. 27, 7220–7235 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Frescas, D., Guardavaccaro, D., Bassermann, F., Koyama-Nasu, R. & Pagano, M. JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes. Nature 450, 309–313 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. He, J., Kallin, E. M., Tsukada, Y. & Zhang, Y. The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15Ink4b. Nature Struct. Mol. Biol. 15, 1169–1175 (2008).

    Article  CAS  Google Scholar 

  102. Tzatsos, A., Pfau, R., Kampranis, S. C. & Tsichlis, P. N. Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc. Natl Acad. Sci. USA 106, 2641–2646 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Pfau, R. et al. Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process. Proc. Natl Acad. Sci. USA 105, 1907–1912 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genet. 41, 521–523 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Barradas, M. et al. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 23, 1177–1182 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Agger, K. et al. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 23, 1171–1176 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  108. Kotake, Y., Zeng, Y. & Xiong, Y. DDB1–CUL4 and MLL1 mediate oncogene-induced p16INK4a activation. Cancer Res. 69, 1809–1814 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Pasini, D. et al. Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-repressive complex 2. Genes Dev. 22, 1345–1355 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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).

    Article  CAS  PubMed  Google Scholar 

  111. Muntean, A. G., Giannola, D., Udager, A. M. & Hess, J. L. The PHD fingers of MLL block MLL fusion protein-mediated transformation. Blood 112, 4690–4693 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chen, J. et al. Loss of MLL PHD finger 3 is necessary for MLL–ENL-induced hematopoietic stem cell immortalization. Cancer Res. 68, 6199–6207 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Perissi, V., Jepsen, K., Glass, C. K. & Rosenfeld, M. G. Deconstructing repression: evolving models of co-repressor action. Nature Rev. Genet. 11, 109–123 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  115. Wu, S. C. & Zhang, Y. Minireview: role of protein methylation and demethylation in nuclear hormone signaling. Mol. Endocrinol. 23, 1323–1334 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang, K. & Dent, S. Y. Histone modifying enzymes and cancer: going beyond histones. J. Cell. Biochem. 96, 1137–1148 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Minucci, S. & Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Rev. Cancer 6, 38–51 (2006).

    Article  CAS  Google Scholar 

  118. Lee, M. J., Kim, Y. S., Kummar, S., Giaccone, G. & Trepel, J. B. Histone deacetylase inhibitors in cancer therapy. Curr. Opin. Oncol. 20, 639–649 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Martens, J. H. et al. PML–RARα/RXR alters the epigenetic landscape in acute promyelocytic leukemia. Cancer Cell 17, 173–185 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Bienz, M. The PHD finger, a nuclear protein-interaction domain. Trends Biochem. Sci. 31, 35–40 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Shi, X. et al. Proteome-wide analysis in Saccharomyces cerevisiae identifies several PHD fingers as novel direct and selective binding modules of histone H3 methylated at either lysine 4 or lysine 36. J. Biol. Chem. 282, 2450–2455 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Peng, J. & Wysocka, J. It takes a PHD to SUMO. Trends Biochem. Sci. 33, 191–194 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Kotake, Y. et al. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4α tumor suppressor gene. Genes Dev. 21, 49–54 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bracken, A. P. et al. The Polycomb group proteins bind throughout the INK4A–ARF locus and are disassociated in senescent cells. Genes Dev. 21, 525–530 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Funding for C.D.A. is provided by the US National Institutes of Health Merit Grant GM53512, a Specialized Center of Research (SCOR) award from the Leukemia and Lymphoma Society, and a grant from the Starr Cancer Consortium. P.C. is a Medical Oncology fellow of Memorial Sloan-Kettering Cancer Center, and G.G.W. is a Leukemia and Lymphoma Society Fellow. We thank A. Ruthenburg and Z. Wang for the critical reading of this manuscript and help with illustration.

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  1. Laboratory of Chromatin Biology and Epigenetics, 1230 York Avenue, The Rockefeller University, BOX 78, New York, 10065, NY, USA

    Ping Chi, C. David Allis & Gang Greg Wang

  2. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, 10021, NY, USA

    Ping Chi

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Glossary

Chromatin

The composition of DNA and proteins (mainly histones) that form chromosomes. It is organized as repeating subunits of nucleosomal core particles that comprise approximately 147 base pairs of DNA wrapped around a histone octamer containing two copies each of histones H2A, H2B, H3 and H4.

Epigenetic

Refers to the study of mechanisms underlying inheritable phenotypic variations caused by DNA sequence-independent alterations. This term has been more loosely used to describe alterations caused by a change of chromatin structure, which often have unclear heritability.

DNA methylation

A type of chemical modification of DNA that involves the addition of a methyl group to the number 5 carbon of the cytosine pyrimidine ring.

Histone methylation

A chemical modification involving the addition of one, two or three methyl groups on the lysine or arginine residues in a histone protein.

General transcription machinery

A large protein complex including RNA polymerase II and general transcription factors such as TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH.

V(D)J recombinase

An enzyme that carries out V(D)J recombination, a specialized DNA rearrangement that randomly selects and assembles the Variable (V), Diversity (D) and Joining (J) gene fragments of immunoglobulin (Ig)- or T cell receptor (TCR)-encoding loci, thus generating a repertoire of Ig or TCR molecules in lymphocytes and a diverse immune response.

Gene rearrangement

Alteration of chromosomes such as a chromosomal translocation that causes changes in gene structural composition or organization. It can occur as a normal developmental event such as during V(D)J recombination, but is more commonly found in cancer cells as chromosomal abnormalities.

Transcription elongation

Efficient transcription and productive RNA processing after RNA polymerase II (Pol II) and associated factors have escaped from abortive initiation, a phenomenon in which Pol II and transcription are halted at promoter-proximal pause sites.

Chromatin dynamics

A fine-tuning mechanism that introduces meaningful variations to chromatin and/or modulate chromatin structure, which includes DNA methylation, covalent histone modification, ATP-dependent chromatin remodelling and the use of histone variants.

Chromatin boundary factor

A factor that interacts with chromatin boundary elements to ensure the appropriate physical separation of chromatin regions that have distinct properties such as regions of active versus silenced transcription. One example is CTCF, a protein that binds to insulator cis-elements.

Multiple osteochondroma

A skeletal disease characterized by the development of benign cartilage-capped bone tumours growing outwards from the bone surface, resulting in various orthopaedic deformities.

Syngeneic tumour transplantation model

A model of tumorigenesis produced by inoculating mouse or rat tumour cells into a corresponding immunocompetent mouse or rat. Syngeneic tumour models have a normal host immune response and tumour microenvironment, and therefore more closely resemble a biologically relevant situation than xenograft models that use immunodeficient mice.

Next-generation sequencing

A still-developing technology to sequence DNA in a massively parallel fashion, therefore sequencing is achieved at a much faster speed and lower cost than traditional gel-based methods. This technology makes direct sequencing of large numbers of human patient samples possible, including those from cancers.

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Chi, P., Allis, C. & Wang, G. Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10, 457–469 (2010). https://doi.org/10.1038/nrc2876

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