Histone lysine methyltransferases in biology and disease.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
18
07
2019
accepted:
12
08
2019
revised:
05
08
2019
entrez:
5
10
2019
pubmed:
5
10
2019
medline:
12
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31582846
doi: 10.1038/s41594-019-0298-7
pii: 10.1038/s41594-019-0298-7
pmc: PMC6951022
mid: NIHMS1066370
doi:
Substances chimiques
Histones
0
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
880-889Subventions
Organisme : NCI NIH HHS
ID : R01 CA236118
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM079641
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG047126
Pays : United States
Références
Murn, J. & Shi, Y. The winding path of protein methylation research: milestones and new frontiers. Nat. Rev. Mol. Cell Biol. 18, 517–527 (2017).
pubmed: 28512349
doi: 10.1038/nrm.2017.35
Carlson, S. M. & Gozani, O. Nonhistone lysine methylation in the regulation of cancer pathways. Cold Spring Harb. Perspect. Med. 6, a026435 (2016).
pubmed: 27580749
pmcid: 5088510
doi: 10.1101/cshperspect.a026435
Clarke, S. G. Protein methylation at the surface and buried deep: thinking outside the histone box. Trends Biochem. Sci. 38, 243–252 (2013).
pubmed: 23490039
pmcid: 23490039
doi: 10.1016/j.tibs.2013.02.004
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).
doi: 10.1002/cpps.16
Ambler, R. P. & Rees, M. W. ε-N-Methyl-lysine in bacterial flagellar protein. Nature 184, 56–57 (1959).
doi: 10.1038/184056b0
Murray, K. The occurrence of epsilon-N-methyl lysine in histones. Biochemistry 3, 10–15 (1964).
doi: 10.1021/bi00889a003
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).
pubmed: 21925322
pmcid: 3176443
doi: 10.1016/j.cell.2011.08.008
Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).
doi: 10.1038/35020506
Elgin, S. C. & Reuter, G. Position-effect variegation, heterochromatin formation, and gene silencing in Drosophila. Cold Spring Harb. Perspect. Biol. 5, a017780 (2013).
pubmed: 23906716
pmcid: 3721279
doi: 10.1101/cshperspect.a017780
Wilkinson, A. W. et al. SETD3 is an actin histidine methyltransferase that prevents primary dystocia. Nature 565, 372–376 (2019).
pubmed: 30626964
doi: 10.1038/s41586-018-0821-8
Petrossian, T. C. & Clarke, S. G. Uncovering the human methyltransferasome. Mol. Cell. Proteom. 10, M110.000976 (2011).
doi: 10.1074/mcp.M110.000976
Kuo, A. J. et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol. Cell 44, 609–620 (2011).
pubmed: 22099308
pmcid: 3222870
doi: 10.1016/j.molcel.2011.08.042
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).
pubmed: 18157086
doi: 10.1038/sj.emboj.7601967
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).
pubmed: 18676810
pmcid: 18676810
doi: 10.1101/gad.476008
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).
pubmed: 22345514
pmcid: 3289880
doi: 10.1101/gad.177444.111
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).
pubmed: 3321094
pmcid: 3321094
doi: 10.1038/nature10956
McKay, D. J. et al. Interrogating the function of metazoan histones using engineered gene clusters. Dev. Cell 32, 373–386 (2015).
pubmed: 25669886
pmcid: 4385256
doi: 10.1016/j.devcel.2014.12.025
Kaniskan, H. U. & Jin, J. Recent progress in developing selective inhibitors of protein methyltransferases. Curr. Opin. Chem. Biol. 39, 100–108 (2017).
pubmed: 28662389
pmcid: 5624721
doi: 10.1016/j.cbpa.2017.06.013
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).
pubmed: 25795785
pmcid: 4424340
doi: 10.1074/jbc.M115.641530
Mazur, P. K. et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510, 283–287 (2014).
pubmed: 4122675
pmcid: 4122675
doi: 10.1038/nature13320
Roqueta-Rivera, M. et al. SETDB2 links glucocorticoid to lipid metabolism through Insig2a regulation. Cell Metab. 24, 474–484 (2016).
pubmed: 27568546
pmcid: 5023502
doi: 10.1016/j.cmet.2016.07.025
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).
pubmed: 27812132
pmcid: 5094779
doi: 10.1371/journal.pone.0165139
Fujiki, R. et al. Retraction: GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature 505, 574 (2014).
doi: 10.1038/nature12896
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).
pubmed: 27864380
pmcid: 5201031
doi: 10.1242/dev.141465
Deliu, E. et al. Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. Nat. Neurosci. 21, 1717–1727 (2018).
pubmed: 30455454
doi: 10.1038/s41593-018-0266-2
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).
pubmed: 21187428
doi: 10.1073/pnas.1013571108
Huang, J. et al. Repression of p53 activity by Smyd2-mediated methylation. Nature 444, 629–632 (2006).
doi: 10.1038/nature05287
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).
pubmed: 16477022
doi: 10.1073/pnas.0509503103
Stender, J. D. et al. Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20. Mol. Cell 48, 28–38 (2012).
pubmed: 22921934
pmcid: 22921934
doi: 10.1016/j.molcel.2012.07.020
Eom, G. H. et al. Histone methyltransferase SETD3 regulates muscle differentiation. J. Biol. Chem. 286, 34733–34742 (2011).
pubmed: 21832073
pmcid: 3186363
doi: 10.1074/jbc.M110.203307
Fog, C. K., Galli, G. G. & Lund, A. H. PRDM proteins: important players in differentiation and disease. BioEssays 34, 50–60 (2012).
pubmed: 22028065
doi: 10.1002/bies.201100107
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
pubmed: 17320507
pmcid: 17320507
doi: 10.1016/j.cell.2007.02.005
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).
pubmed: 31147750
doi: 10.1007/s00018-019-03144-y
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).
pubmed: 25093525
doi: 10.1038/nsmb.2866
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).
pubmed: 4363072
pmcid: 4363072
doi: 10.1016/j.molcel.2014.08.022
Wen, H. et al. ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature 508, 263–268 (2014).
pubmed: 4142212
pmcid: 4142212
doi: 10.1038/nature13045
Baubec, T. et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520, 243–247 (2015).
pubmed: 25607372
doi: 10.1038/nature14176
Blackledge, N. P. et al. CpG islands recruit a histone H3 lysine 36 demethylase. Mol. Cell 38, 179–190 (2010).
pubmed: 20417597
pmcid: 3098377
doi: 10.1016/j.molcel.2010.04.009
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).
pubmed: 28193767
pmcid: 5453381
doi: 10.1101/cshperspect.a026708
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).
doi: 10.1158/0008-5472.CAN-10-0120
Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).
pubmed: 2820242
pmcid: 2820242
doi: 10.1038/nature08672
Collisson, E. A. et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
doi: 10.1038/nature13385
Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).
pubmed: 3267575
pmcid: 3267575
doi: 10.1038/nature10725
Zhu, X. et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat. Genet. 46, 287–293 (2014).
pubmed: 24509477
pmcid: 4440318
doi: 10.1038/ng.2894
Parker, H. et al. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia 30, 2179–2186 (2016).
pubmed: 27282254
pmcid: 5023049
doi: 10.1038/leu.2016.134
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).
pubmed: 27600764
pmcid: 5023950
doi: 10.1038/ncomms12602
McKinney, M. et al. The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discov. 7, 369–379 (2017).
pubmed: 28122867
pmcid: 5402251
doi: 10.1158/2159-8290.CD-16-0330
Martinelli, G. et al. SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis. Leukemia 32, 139–148 (2018).
pubmed: 28663576
doi: 10.1038/leu.2017.183
Viaene, A. N. et al. SETD2 mutations in primary central nervous system tumors. Acta Neuropathol. Commun. 6, 123 (2018).
pubmed: 30419952
pmcid: 6231273
doi: 10.1186/s40478-018-0623-0
Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43, 875–878 (2011).
pubmed: 5373841
pmcid: 5373841
doi: 10.1038/ng.907
Huang, K. K. et al. SETD2 histone modifier loss in aggressive GI stromal tumours. Gut 65, 1960–1972 (2016).
pubmed: 26338826
doi: 10.1136/gutjnl-2015-309482
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
pubmed: 4878653
pmcid: 4878653
doi: 10.1056/NEJMoa1113205
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).
pubmed: 3708609
pmcid: 3708609
doi: 10.1158/1078-0432.CCR-12-3886
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).
pubmed: 26111976
pmcid: 4556533
doi: 10.1038/modpathol.2015.68
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).
pubmed: 24662245
pmcid: 4016990
doi: 10.1038/ncomms4469
Lee, J. J.-K. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019).
pubmed: 31155235
doi: 10.1016/j.cell.2019.05.013
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).
pubmed: 21828136
pmcid: 3208280
doi: 10.1182/blood-2011-03-343947
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).
pubmed: 24316982
doi: 10.1038/ng.2847
March, H. N. et al. Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis. Nat. Genet. 43, 1202–1209 (2011).
pubmed: 22057237
pmcid: 3233530
doi: 10.1038/ng.990
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).
pubmed: 28530655
pmcid: 5495136
doi: 10.1038/nmeth.4297
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).
pubmed: 28202515
pmcid: 5380596
doi: 10.1158/0008-5472.CAN-16-2159
Xu, Q. et al. SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development. Nat. Genet. 51, 844–856 (2019).
pubmed: 31040401
doi: 10.1038/s41588-019-0398-7
Li, F. et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 153, 590–600 (2013).
pubmed: 3641580
pmcid: 3641580
doi: 10.1016/j.cell.2013.03.025
Park, I. Y. et al. Dual chromatin and cytoskeletal remodeling by SETD2. Cell 166, 950–962 (2016).
pubmed: 27518565
pmcid: 5101839
doi: 10.1016/j.cell.2016.07.005
Chen, K. et al. Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity. Cell 170, 492–506.e14 (2017).
pubmed: 28753426
doi: 10.1016/j.cell.2017.06.042
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).
pubmed: 19808676
pmcid: 19808676
doi: 10.1074/jbc.M109.034462
Papillon-Cavanagh, S. et al. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nat. Genet. 49, 180–185 (2017).
pubmed: 28067913
pmcid: 5549104
doi: 10.1038/ng.3757
Zhu, L. et al. ASH1L links histone H3 lysine 36 dimethylation to MLL leukemia. Cancer Discov. 6, 770–783 (2016).
pubmed: 27154821
pmcid: 4930721
doi: 10.1158/2159-8290.CD-16-0058
Anderson, K. C. & Carrasco, R. D. Pathogenesis of myeloma. Annu. Rev. Pathol. 6, 249–274 (2011).
pubmed: 21261519
doi: 10.1146/annurev-pathol-011110-130249
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).
pubmed: 18070707
pmcid: 2198931
doi: 10.1016/j.beha.2007.08.004
Palumbo, A. & Anderson, K. Multiple myeloma. N. Engl. J. Med. 364, 1046–1060 (2011).
pubmed: 21410373
doi: 10.1056/NEJMra1011442
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).
pubmed: 12393535
doi: 10.1182/blood-2002-06-1675
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).
pubmed: 12433679
doi: 10.1182/blood-2002-09-2801
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).
pubmed: 9787135
Aytes, A. et al. NSD2 is a conserved driver of metastatic prostate cancer progression. Nat. Commun. 9, 5201 (2018).
pubmed: 30518758
pmcid: 6281610
doi: 10.1038/s41467-018-07511-4
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).
pubmed: 3037745
pmcid: 3037745
doi: 10.1182/blood-2010-07-298349
Jaffe, J. D. et al. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat. Genet. 45, 1386–1391 (2013).
pubmed: 24076604
pmcid: 4262138
doi: 10.1038/ng.2777
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).
pubmed: 23823660
doi: 10.1038/leu.2013.204
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).
Huang, C. & Zhu, B. Roles of H3K36-specific histone methyltransferases in transcription: antagonizing silencing and safeguarding transcription fidelity. Biophys. Rep. 4, 170–177 (2018).
pubmed: 30310854
pmcid: 6153486
doi: 10.1007/s41048-018-0063-1
Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).
doi: 10.1158/2159-8290.CD-12-0095
Sankaran, S. M. & Gozani, O. Characterization of H3.3K36M as a tool to study H3K36 methylation in cancer cells. Epigenetics 12, 917–922 (2017).
pubmed: 28933651
pmcid: 5788406
doi: 10.1080/15592294.2017.1377870
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).
pubmed: 26912663
pmcid: 4861420
doi: 10.1074/jbc.M116.720748
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).
pubmed: 17589499
doi: 10.1038/ncb1608
Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).
doi: 10.1038/nature14129
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).
pubmed: 19380029
doi: 10.1016/j.cancergencyto.2008.12.008
Shen, C. et al. NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler. Mol. Cell 60, 847–859 (2015).
pubmed: 26626481
pmcid: 4688131
doi: 10.1016/j.molcel.2015.10.033
Kurotaki, N. et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat. Genet. 30, 365–366 (2002).
pubmed: 11896389
doi: 10.1038/ng863
Gibson, W. T. et al. Mutations in EZH2 cause Weaver syndrome. Am. J. Hum. Genet. 90, 110–118 (2012).
pubmed: 22177091
pmcid: 3257956
doi: 10.1016/j.ajhg.2011.11.018
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).
pubmed: 12464997
doi: 10.1086/345647
Tlemsani, C. et al. SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J. Med. Genet. 53, 743–751 (2016).
pubmed: 27317772
doi: 10.1136/jmedgenet-2015-103638
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).
pubmed: 23601102
doi: 10.1016/j.chom.2013.03.004
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).
pubmed: 31061526
doi: 10.1038/s41594-019-0219-9
Reynoird, N. et al. Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. Genes Dev. 30, 772–785 (2016).
pubmed: 26988419
pmcid: 4826394
doi: 10.1101/gad.275529.115
Hamamoto, R. et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat. Cell Biol. 6, 731–740 (2004).
pubmed: 15235609
doi: 10.1038/ncb1151
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).
doi: 10.1158/0008-5472.CAN-07-1132
Pinheiro, I. et al. Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. Cell 150, 948–960 (2012).
pubmed: 22939622
pmcid: 22939622
doi: 10.1016/j.cell.2012.06.048
Zhou, B. et al. PRDM16 suppresses MLL1r leukemia via intrinsic histone methyltransferase activity. Mol. Cell 62, 222–236 (2016).
pubmed: 27151440
pmcid: 5061593
doi: 10.1016/j.molcel.2016.03.010
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).
pubmed: 21855806
doi: 10.1016/j.molcel.2011.08.007
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).
pubmed: 19074312
doi: 10.1126/science.1163601
Takata, A. et al. Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82, 773–780 (2014).
pubmed: 4387883
pmcid: 4387883
doi: 10.1016/j.neuron.2014.04.043
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).
pubmed: 25550471
doi: 10.1096/fj.14-263061
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).
pubmed: 25428890
doi: 10.1002/ajmg.a.36872
Schmidt, K. et al. The H3K4 methyltransferase Setd1b is essential for hematopoietic stem and progenitor cell homeostasis in mice. eLife 7, e27157 (2018).
pubmed: 29916805
pmcid: 6025962
doi: 10.7554/eLife.27157
Jones, W. D. et al. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am. J. Hum. Genet. 91, 358–364 (2012).
pubmed: 3415539
pmcid: 3415539
doi: 10.1016/j.ajhg.2012.06.008
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).
pubmed: 7477409
pmcid: 7477409
doi: 10.1038/378505a0
Glaser, S. et al. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development 133, 1423–1432 (2006).
doi: 10.1242/dev.02302
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).
doi: 10.1073/pnas.0810100105
Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013).
pubmed: 3869375
pmcid: 3869375
doi: 10.7554/eLife.01503
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).
pubmed: 27839873
pmcid: 5142117
doi: 10.1016/j.ajhg.2016.10.010
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).
doi: 10.1016/j.stem.2007.07.002
Kleefstra, T. et al. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am. J. Hum. Genet. 91, 73–82 (2012).
pubmed: 3397275
pmcid: 3397275
doi: 10.1016/j.ajhg.2012.05.003
Ng, S. B. et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 42, 790–793 (2010).
pubmed: 20711175
pmcid: 20711175
doi: 10.1038/ng.646
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).
pubmed: 12130538
pmcid: 12130538
doi: 10.1101/gad.989402
Schaefer, A. et al. Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64, 678–691 (2009).
pubmed: 20005824
pmcid: 2814156
doi: 10.1016/j.neuron.2009.11.019
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).
pubmed: 16826528
pmcid: 1559478
doi: 10.1086/505693
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).
pubmed: 15774718
pmcid: 15774718
doi: 10.1101/gad.1284005
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).
pubmed: 24196706
pmcid: 24196706
doi: 10.1038/nature12652
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).
pubmed: 14993285
pmcid: 355869
doi: 10.1128/MCB.24.6.2478-2486.2004
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).
pmcid: 4281561
doi: 10.1101/gad.254425.114
pubmed: 4281561
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).
pubmed: 3049289
pmcid: 3049289
doi: 10.1101/gad.2019811
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).
doi: 10.1016/j.stem.2012.08.001
O’Carroll, D. et al. The polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330–4336 (2001).
pubmed: 11390661
pmcid: 87093
doi: 10.1128/MCB.21.13.4330-4336.2001
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).
pubmed: 12805229
pmcid: 12805229
doi: 10.1093/emboj/cdg288
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).
pubmed: 14997421
pmcid: 1181947
doi: 10.1086/383093
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).
pubmed: 9063753
doi: 10.1093/hmg/6.2.317
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).
pubmed: 29760529
doi: 10.1038/s10038-018-0464-5
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).
pubmed: 30345613
doi: 10.1002/ajmg.a.40498
Nimura, K. et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature 460, 287–291 (2009).
pubmed: 19483677
doi: 10.1038/nature08086
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).
pubmed: 30566865
doi: 10.1016/j.celrep.2018.11.096
Okamoto, N. et al. Novel MCA/ID syndrome with ASH1L mutation. Am. J. Med. Genet. 173, 1644–1648 (2017).
pubmed: 28394464
doi: 10.1002/ajmg.a.38193
Zhu, T. et al. Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α. Sci. Rep. 6, 26597 (2016).
doi: 10.1038/srep26597
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).
Luscan, A. et al. Mutations in SETD2 cause a novel overgrowth condition. J. Med. Genet. 51, 512–517 (2014).
pubmed: 24852293
doi: 10.1136/jmedgenet-2014-102402
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).
pubmed: 26084711
doi: 10.1007/s10803-015-2484-8
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).
pubmed: 20133625
doi: 10.1073/pnas.0915033107
Wang, L. et al. H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells. PLoS Biol. 16, e2006522 (2018).
pubmed: 30422989
pmcid: 6233919
doi: 10.1371/journal.pbio.2006522
Yi, X. et al. Histone methyltransferase Setd2 is critical for the proliferation and differentiation of myoblasts. Biochim. Biophys. Acta 1864, 697–707 (2017).
doi: 10.1016/j.bbamcr.2017.01.012
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).
pubmed: 29716999
pmcid: 6005419
doi: 10.1074/jbc.RA118.002851
Skucha, A. et al. MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. Nat. Commun. 9, 1983 (2018).
pubmed: 29777171
pmcid: 5959866
doi: 10.1038/s41467-018-04329-y
Jones, B. et al. The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLoS Genet. 4, e1000190 (2008).
pubmed: 18787701
pmcid: 18787701
doi: 10.1371/journal.pgen.1000190
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).
pubmed: 3100687
pmcid: 3100687
doi: 10.1182/blood-2010-12-327668
Nguyen, A. T., He, J., Taranova, O. & Zhang, Y. Essential role of DOT1L in maintaining normal adult hematopoiesis. Cell Res. 21, 1370–1373 (2011).
pubmed: 21769133
pmcid: 3166961
doi: 10.1038/cr.2011.115
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).
pubmed: 19223465
pmcid: 19223465
doi: 10.1128/MCB.01768-08
Faundes, V. et al. Histone lysine methylases and demethylases in the landscape of human developmental disorders. Am. J. Hum. Genet. 102, 175–187 (2018).
pubmed: 29276005
doi: 10.1016/j.ajhg.2017.11.013