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Histone lysine methyltransferases in biology and disease

The precise temporal and spatial coordination of histone lysine methylation dynamics across the epigenome regulates virtually all DNA-templated processes. A large number of histone lysine methyltransferase (KMT) enzymes catalyze the various lysine methylation events decorating the core histone proteins. Mutations, genetic translocations and altered gene expression involving these KMTs are frequently observed in cancer, developmental disorders and other pathologies. Therapeutic compounds targeting specific KMTs are currently being tested in the clinic, although overall drug discovery in the field is relatively underdeveloped. Here we review the biochemical and biological activities of histone KMTs and their connections to human diseases, focusing on cancer. We also discuss the scientific and clinical challenges and opportunities in studying KMTs.

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Fig. 1: Main sites of lysine methylation on mammalian histones and chromatin functions.
Fig. 2: Histone KMTs in the human proteome.
Fig. 3: Spectrum of cancers associated with H3K36 methyltransferases.
Fig. 4: Model for crosstalk between methylation at H3K27 and H3K36 in oncogenic programming.

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References

  1. Murn, J. & Shi, Y. The winding path of protein methylation research: milestones and new frontiers. Nat. Rev. Mol. Cell Biol. 18, 517–527 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Carlson, S. M. & Gozani, O. Nonhistone lysine methylation in the regulation of cancer pathways. Cold Spring Harb. Perspect. Med. 6, a026435 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Clarke, S. G. Protein methylation at the surface and buried deep: thinking outside the histone box. Trends Biochem. Sci. 38, 243–252 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cao, X. J. & Garcia, B. A. Global proteomics analysis of protein lysine methylation. Curr. Protoc. Protein Sci. 86, 24.8.1–24.8.19 (2016).

    Article  Google Scholar 

  5. Ambler, R. P. & Rees, M. W. ε-N-Methyl-lysine in bacterial flagellar protein. Nature 184, 56–57 (1959).

    Article  CAS  PubMed  Google Scholar 

  6. Murray, K. The occurrence of epsilon-N-methyl lysine in histones. Biochemistry 3, 10–15 (1964).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Wilkinson, A. W. et al. SETD3 is an actin histidine methyltransferase that prevents primary dystocia. Nature 565, 372–376 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Petrossian, T. C. & Clarke, S. G. Uncovering the human methyltransferasome. Mol. Cell. Proteom. 10, M110.000976 (2011).

    Article  CAS  Google Scholar 

  12. Kuo, A. J. et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol. Cell 44, 609–620 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Edmunds, J. W., Mahadevan, L. C. & Clayton, A. L. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 27, 406–420 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Schotta, G. et al. A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev. 22, 2048–2061 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Beck, D. B., Oda, H., Shen, S. S. & Reinberg, D. PR-Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes Dev. 26, 325–337 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McKay, D. J. et al. Interrogating the function of metazoan histones using engineered gene clusters. Dev. Cell 32, 373–386 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kaniskan, H. U. & Jin, J. Recent progress in developing selective inhibitors of protein methyltransferases. Curr. Opin. Chem. Biol. 39, 100–108 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Carlson, S. M. et al. A proteomic strategy identifies lysine methylation of splicing factor snRNP70 by the SETMAR enzyme. J. Biol. Chem. 290, 12040–12047 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mazur, P. K. et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510, 283–287 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Roqueta-Rivera, M. et al. SETDB2 links glucocorticoid to lipid metabolism through Insig2a regulation. Cell Metab. 24, 474–484 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mas-Y-Mas, S. et al. The human mixed lineage leukemia 5 (MLL5), a sequentially and structurally divergent SET domain-containing protein with no intrinsic catalytic activity. PLoS One 11, e0165139 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Fujiki, R. et al. Retraction: GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature 505, 574 (2014).

    Article  CAS  Google Scholar 

  24. Osipovich, A. B., Gangula, R., Vianna, P. G. & Magnuson, M. A. Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation. Development 143, 4595–4607 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Deliu, E. et al. Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. Nat. Neurosci. 21, 1717–1727 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Fnu, S. et al. Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining. Proc. Natl Acad. Sci. USA 108, 540–545 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Huang, J. et al. Repression of p53 activity by Smyd2-mediated methylation. Nature 444, 629–632 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Tan, X., Rotllant, J., Li, H., De Deyne, P. & Du, S. J. SmyD1, a histone methyltransferase, is required for myofibril organization and muscle contraction in zebrafish embryos. Proc. Natl Acad. Sci. USA 103, 2713–2718 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Stender, J. D. et al. Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20. Mol. Cell 48, 28–38 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Eom, G. H. et al. Histone methyltransferase SETD3 regulates muscle differentiation. J. Biol. Chem. 286, 34733–34742 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fog, C. K., Galli, G. G. & Lund, A. H. PRDM proteins: important players in differentiation and disease. BioEssays 34, 50–60 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Li, J., Ahn, J. H. & Wang, G. G. Understanding histone H3 lysine 36 methylation and its deregulation in disease. Cell. Mol. Life Sci. 76, 2899–2916 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Jha, D. K., Pfister, S. X., Humphrey, T. C. & Strahl, B. D. SET-ting the stage for DNA repair. Nat. Struct. Mol. Biol. 21, 655–657 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Guo, R. et al. BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing. Mol. Cell 56, 298–310 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wen, H. et al. ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature 508, 263–268 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Baubec, T. et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520, 243–247 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bennett, R. L., Swaroop, A., Troche, C. & Licht, J. D. The role of nuclear receptor–binding SET domain family histone lysine methyltransferases in cancer. Cold Spring Harb. Perspect. Med. 7, a026708 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Duns, G. et al. Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma. Cancer Res. 70, 4287–4291 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. 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 

  42. Collisson, E. A. et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

    Article  CAS  Google Scholar 

  43. Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhu, X. et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat. Genet. 46, 287–293 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Parker, H. et al. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia 30, 2179–2186 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Roberti, A. et al. Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations. Nat. Commun. 7, 12602 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  47. McKinney, M. et al. The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discov. 7, 369–379 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Martinelli, G. et al. SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis. Leukemia 32, 139–148 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Viaene, A. N. et al. SETD2 mutations in primary central nervous system tumors. Acta Neuropathol. Commun. 6, 123 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43, 875–878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Huang, K. K. et al. SETD2 histone modifier loss in aggressive GI stromal tumours. Gut 65, 1960–1972 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hakimi, A. A. et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin. Cancer Res. 19, 3259–3267 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Singh, R. R. et al. Intratumoral morphologic and molecular heterogeneity of rhabdoid renal cell carcinoma: challenges for personalized therapy. Mod. Pathol. 28, 1225–1235 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mar, B. G. et al. Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia. Nat. Commun. 5, 3469 (2014).

    Article  PubMed  CAS  Google Scholar 

  56. Lee, J. J.-K. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019).

    Article  CAS  PubMed  Google Scholar 

  57. Berquam-Vrieze, K. E. et al. Cell of origin strongly influences genetic selection in a mouse model of T-ALL. Blood 118, 4646–4656 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bard-Chapeau, E. A. et al. Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model. Nat. Genet. 46, 24–32 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. March, H. N. et al. Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis. Nat. Genet. 43, 1202–1209 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rogers, Z. N. et al. A quantitative and multiplexed approach to uncover the fitness landscape of tumor suppression in vivo. Nat. Methods 14, 737–742 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Walter, D. M. et al. Systematic in vivo inactivation of chromatin-regulating enzymes identifies Setd2 as a potent tumor suppressor in lung adenocarcinoma. Cancer Res. 77, 1719–1729 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. Li, F. et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 153, 590–600 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Park, I. Y. et al. Dual chromatin and cytoskeletal remodeling by SETD2. Cell 166, 950–962 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen, K. et al. Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity. Cell 170, 492–506.e14 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Li, Y. et al. The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate. J. Biol. Chem. 284, 34283–34295 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Papillon-Cavanagh, S. et al. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nat. Genet. 49, 180–185 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhu, L. et al. ASH1L links histone H3 lysine 36 dimethylation to MLL leukemia. Cancer Discov. 6, 770–783 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Anderson, K. C. & Carrasco, R. D. Pathogenesis of myeloma. Annu. Rev. Pathol. 6, 249–274 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Chng, W. J., Glebov, O., Bergsagel, P. L. & Kuehl, W. M. Genetic events in the pathogenesis of multiple myeloma. Best. Pract. Res. Clin. Haematol. 20, 571–596 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Palumbo, A. & Anderson, K. Multiple myeloma. N. Engl. J. Med. 364, 1046–1060 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Keats, J. J. et al. In multiple myeloma, t(4;14)(p16; q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101, 1520–1529 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Santra, M., Zhan, F., Tian, E., Barlogie, B. & Shaughnessy, J. Jr. A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 101, 2374–2376 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Chesi, M. et al. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92, 3025–3034 (1998).

    CAS  PubMed  Google Scholar 

  75. Aytes, A. et al. NSD2 is a conserved driver of metastatic prostate cancer progression. Nat. Commun. 9, 5201 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Martinez-Garcia, E. et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 117, 211–220 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jaffe, J. D. et al. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat. Genet. 45, 1386–1391 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Oyer, J. A. et al. Point mutation E1099K in MMSET/NSD2 enhances its methyltransferase activity and leads to altered global chromatin methylation in lymphoid malignancies. Leukemia 28, 198–201 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Carroll, W.L. et al. Pediatric acute lymphoblastic leukemia. in ASH Education: Hematology 2003, 102–131 https://doi.org/10.1182/asheducation-2003.1.102 (2003).

  80. Huang, C. & Zhu, B. Roles of H3K36-specific histone methyltransferases in transcription: antagonizing silencing and safeguarding transcription fidelity. Biophys. Rep. 4, 170–177 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  PubMed  Google Scholar 

  82. Sankaran, S. M. & Gozani, O. Characterization of H3.3K36M as a tool to study H3K36 methylation in cancer cells. Epigenetics 12, 917–922 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Sankaran, S. M., Wilkinson, A. W., Elias, J. E. & Gozani, O. A PWWP domain of histone-lysine N-methyltransferase NSD2 binds to dimethylated Lys-36 of histone H3 and regulates NSD2 function at chromatin. J. Biol. Chem. 291, 8465–8474 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang, G. G., Cai, L., Pasillas, M. P. & Kamps, M. P. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat. Cell Biol. 9, 804–812 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).

    Article  CAS  Google Scholar 

  86. Taketani, T. et al. NUP98-NSD3 fusion gene in radiation-associated myelodysplastic syndrome with t(8;11)(p11; p15) and expression pattern of NSD family genes. Cancer Genet. Cytogenet. 190, 108–112 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Shen, C. et al. NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler. Mol. Cell 60, 847–859 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kurotaki, N. et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat. Genet. 30, 365–366 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Gibson, W. T. et al. Mutations in EZH2 cause Weaver syndrome. Am. J. Hum. Genet. 90, 110–118 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Douglas, J. et al. NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. Am. J. Hum. Genet. 72, 132–143 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Tlemsani, C. et al. SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J. Med. Genet. 53, 743–751 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Rolando, M. et al. Legionella pneumophila effector RomA uniquely modifies host chromatin to repress gene expression and promote intracellular bacterial replication. Cell Host Microbe 13, 395–405 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Metzger, E. et al. KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells. Nat. Struct. Mol. Biol. 26, 361–371 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Reynoird, N. et al. Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. Genes Dev. 30, 772–785 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hamamoto, R. et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat. Cell Biol. 6, 731–740 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Kunizaki, M. et al. The lysine 831 of vascular endothelial growth factor receptor 1 is a novel target of methylation by SMYD3. Cancer Res. 67, 10759–10765 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Pinheiro, I. et al. Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. Cell 150, 948–960 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Zhou, B. et al. PRDM16 suppresses MLL1r leukemia via intrinsic histone methyltransferase activity. Mol. Cell 62, 222–236 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Campaner, S. et al. The methyltransferase Set7/9 (Setd7) is dispensable for the p53-mediated DNA damage response in vivo. Mol. Cell 43, 681–688 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Mihola, O., Trachtulec, Z., Vlcek, C., Schimenti, J. C. & Forejt, J. A mouse speciation gene encodes a meiotic histone H3 methyltransferase. Science 323, 373–375 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Takata, A. et al. Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82, 773–780 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tusi, B. K. et al. Setd1a regulates progenitor B-cell-to-precursor B-cell development through histone H3 lysine 4 trimethylation and Ig heavy-chain rearrangement. FASEB J. 29, 1505–1515 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Palumbo, O. et al. Microdeletion of 12q24.31: report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms. Am. J. Med. Genet. A. 167A, 438–444 (2015).

    Article  PubMed  CAS  Google Scholar 

  104. Schmidt, K. et al. The H3K4 methyltransferase Setd1b is essential for hematopoietic stem and progenitor cell homeostasis in mice. eLife 7, e27157 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Jones, W. D. et al. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am. J. Hum. Genet. 91, 358–364 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yu, B. D., Hess, J. L., Horning, S. E., Brown, G. A. J. & Korsmeyer, S. J. Altered Hox expression and segmental identity in Mll-mutant mice. Nature 378, 505–508 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Glaser, S. et al. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development 133, 1423–1432 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Lee, J. et al. Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis. Proc. Natl Acad. Sci. USA 105, 19229–19234 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Zech, M. et al. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am. J. Hum. Genet. 99, 1377–1387 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. McMahon, K. A. et al. Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell 1, 338–345 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Kleefstra, T. et al. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am. J. Hum. Genet. 91, 73–82 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ng, S. B. et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 42, 790–793 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779–1791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Schaefer, A. et al. Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64, 678–691 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kleefstra, T. et al. Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am. J. Hum. Genet. 79, 370–377 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tachibana, M. et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 19, 815–826 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ohno, H., Shinoda, K., Ohyama, K., Sharp, L. Z. & Kajimura, S. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504, 163–167 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Dodge, J. E., Kang, Y. K., Beppu, H., Lei, H. & Li, E. Histone H3-K9 methyltransferase ESET is essential for early development. Mol. Cell. Biol. 24, 2478–2486 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Liu, S. et al. Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells. Genes Dev. 29, 108 (2015).

    Article  PubMed Central  CAS  Google Scholar 

  121. Ezhkova, E. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hidalgo, I. et al. Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest. Cell Stem Cell 11, 649–662 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. O’Carroll, D. et al. The polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330–4336 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Rayasam, G. V. et al. NSD1 is essential for early post-implantation development and has a catalytically active SET domain. EMBO J. 22, 3153–3163 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Baujat, G. et al. Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome. Am. J. Hum. Genet. 74, 715–720 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wright, T. J. et al. A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum. Mol. Genet. 6, 317–324 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Lozier, E. R. et al. De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features. J. Hum. Genet. 63, 919–922 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Boczek, N. J. et al. Developmental delay and failure to thrive associated with a loss-of-function variant in WHSC1 (NSD2). Am. J. Med. Genet. A. 176, 2798–2802 (2018).

    Article  CAS  PubMed  Google Scholar 

  129. Nimura, K. et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature 460, 287–291 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Chen, J. et al. Methyltransferase Nsd2 ensures germinal center selection by promoting adhesive interactions between B cells and follicular dendritic cells. Cell Rep. 25, 3393–3404.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  131. Okamoto, N. et al. Novel MCA/ID syndrome with ASH1L mutation. Am. J. Med. Genet. 173, 1644–1648 (2017).

    Article  CAS  PubMed  Google Scholar 

  132. Zhu, T. et al. Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α. Sci. Rep. 6, 26597 (2016).

    Article  CAS  Google Scholar 

  133. Jih, G. et al. The Trithorax-group protein ASH1L regulates hematopoietic stem cell homeostasis independently of its histone methyltransferase activity. Blood 132(Suppl. 1), 1270 (2018).

    Google Scholar 

  134. Luscan, A. et al. Mutations in SETD2 cause a novel overgrowth condition. J. Med. Genet. 51, 512–517 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Lumish, H. S., Wynn, J., Devinsky, O. & Chung, W. K. SETD2 mutation in a child with autism, intellectual disabilities and epilepsy. J. Autism Dev. Disord. 45, 3764–3770 (2015).

    Article  PubMed  Google Scholar 

  136. Hu, M. et al. Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. Proc. Natl Acad. Sci. USA 107, 2956–2961 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wang, L. et al. H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells. PLoS Biol. 16, e2006522 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Yi, X. et al. Histone methyltransferase Setd2 is critical for the proliferation and differentiation of myoblasts. Biochim. Biophys. Acta 1864, 697–707 (2017).

    Article  CAS  Google Scholar 

  139. Zuo, X. et al. The histone methyltransferase SETD2 is required for expression of acrosin-binding protein 1 and protamines and essential for spermiogenesis in mice. J. Biol. Chem. 293, 9188–9197 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Skucha, A. et al. MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. Nat. Commun. 9, 1983 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Jones, B. et al. The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLoS Genet. 4, e1000190 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Jo, S. Y., Granowicz, E. M., Maillard, I., Thomas, D. & Hess, J. L. Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. Blood 117, 4759–4768 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Nguyen, A. T., He, J., Taranova, O. & Zhang, Y. Essential role of DOT1L in maintaining normal adult hematopoiesis. Cell Res. 21, 1370–1373 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Oda, H. et al. Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development. Mol. Cell. Biol. 29, 2278–2295 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Faundes, V. et al. Histone lysine methylases and demethylases in the landscape of human developmental disorders. Am. J. Hum. Genet. 102, 175–187 (2018).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by grants from the US National Institutes of Health to O.G. (R01GM079641). D.H. is supported by T32 AG0047126.

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Correspondence to Or Gozani.

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O.G. is a cofounder of Epicypher, Inc., and Athelas Therapeutics, Inc.

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Peer review information Anke Sparmann was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Husmann, D., Gozani, O. Histone lysine methyltransferases in biology and disease. Nat Struct Mol Biol 26, 880–889 (2019). https://doi.org/10.1038/s41594-019-0298-7

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