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Histone H3K36 methylation is well-known for its role in active transcription. In Saccharomyces cerevisiae, H3K36 methylation is mediated solely by SET2 during transcription elongation. In metazoans, multiple H3K36-specific methyltransferases exist and contribute to distinct biochemical activities and subsequent functions. In this review, we focus on the H3K36-specific histone methyltransferases in metazoans, and discuss their enzymatic activity regulation and their roles in antagonizing Polycomb silencing and safeguarding transcription fidelity.
An S, Yeo KJ, Jeon YH, Song JJ, (2011) Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism.J Biol Chem 286:8369-8374
Antonysamy S, Condon B, Druzina Z, Bonanno JB, Gheyi T, Zhang F, MacEwan I, Zhang A, Ashok S, Rodgers L, Russell M, Gately LuzJ, (2013) Structural context of disease-associated mutations and putative mechanism of autoinhibition revealed by X-ray crystallographic analysis of the EZH2-SET domain.PLoS ONE 8:e84147
Bell O, Wirbelauer C, Hild M, Scharf AN, Schwaiger M, MacAlpine DM, Zilbermann F, van Leeuwen F, Bell SP, Imhof A, Garza D, Peters AH, Schübeler D, (2007) Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila.EMBO J 26:4974-4984
Bender LB, Suh J, Carroll CR, Fong Y, Fingerman IM, Briggs SD, Cao R, Zhang Y, Reinke V, Strome S, (2006) MES-4: an autosome-associated histone methyltransferase that participates in silencing the X chromosomes in the C. elegans germ line.Development 133:3907-3917
Bennett RL, Swaroop A, Troche C, Licht JD, (2017) The role of nuclear receptor-binding SET domain family histone lysine methyltransferases in cancer.Cold Spring Harb Perspect Med
Brooun A, Gajiwala KS, Deng YL, Liu W, Bolanos B, Bingham P, He YA, Diehl W, Grable N, Kung PP, Sutton S, Maegley KA, Yu X, Stewart AE, (2016) Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance.Nat Commun 7:11384
Byrd KN, Shearn A, (2003) ASH1, a Drosophila trithorax group protein, is required for methylation of lysine 4 residues on histone H3.Proc Natl Acad Sci USA 100:11535-11540
Carrozza MJ, Li B, Florens L, Suganuma T, Swanson SK, Lee KK, Shia WJ, Anderson S, Yates J, Washburn MP, Workman JL, (2005) Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription.Cell 123:581-592
Dorighi KM, Tamkun JW, (2013) The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to counteract Polycomb group repression in Drosophila.Development 140:4182-4192
Edmunds JW, Mahadevan LC, Clayton AL, (2008) Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation.EMBO J 27:406-420
Fahey CC, Davis IJ, (2017) SETting the stage for cancer development: SETD2 and the consequences of lost methylation.Cold Spring Harb Perspect Med
Fang D, Gan H, Lee JH, Han J, Wang Z, Riester SM, Jin L, Chen J, Zhou H, Wang J, Zhang H, Yang N, Bradley EW, Ho TH, Rubin BP, Bridge JA, Thibodeau SN, Ordog T, Chen Y, van Wijnen AJ, Oliveira AM, Xu RM, Westendorf JJ, Zhang Z, (2016) The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas.Science 352:1344-1348
Fong Y, Bender L, Wang W, Strome S, (2002) Regulation of the different chromatin states of autosomes and X chromosomes in the germ line of C. elegans.Science 296:2235-2238
Gaydos LJ, Rechtsteiner A, Egelhofer TA, Carroll CR, Strome S, (2012) Antagonism between MES-4 and Polycomb repressive complex 2 promotes appropriate gene expression in C. elegans germ cells.Cell Rep 2:1169-1177
Gregory GD, Vakoc CR, Rozovskaia T, Zheng X, Patel S, Nakamura T, Canaani E, Blobel GA, (2007) Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes.Mol Cell Biol 27:8466-8479
He C, Li F, Zhang J, Wu J, Shi Y, (2013) The methyltransferase NSD3 has chromatin-binding motifs, PHD5-C5HCH, that are distinct from other NSD (nuclear receptor SET domain) family members in their histone H3 recognition.J Biol Chem 288:4692-4703
Huang N, vom Baur E, Garnier JM, Lerouge T, Vonesch JL, Lutz Y, Chambon P, Losson R, (1998) Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators.EMBO J 17:3398-3412
Huang C, Yang F, Zhang Z, Zhang J, Cai G, Li L, Zheng Y, Chen S, Xi R, Zhu B, (2017) Mrg15 stimulates Ash1 H3K36 methyltransferase activity and facilitates Ash1 Trithorax group protein function inDrosophila.Nat Commun 8:1649
Jiao L, Liu X, (2015) Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2.Science 350:aac4383
Jones PA, (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond.Nat Rev Genet 13:484-492
Joshi AA, Struhl K, (2005) Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation.Mol Cell 20:971-978
Justin N, Zhang Y, Tarricone C, Martin SR, Chen S, Underwood E, De Marco V, Haire LF, Walker PA, Reinberg D, Wilson JR, Gamblin SJ, (2016) Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2.Nat Commun 7:11316
Keogh MC, Kurdistani SK, Morris SA, Ahn SH, Podolny V, Collins SR, Schuldiner M, Chin K, Punna T, Thompson NJ, Boone C, Emili A, Weissman JS, Hughes TR, Strahl BD, Grunstein M, Greenblatt JF, Buratowski S, Krogan NJ, (2005) Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex.Cell 123:593-605
Kouzarides T, (2007) Chromatin modifications and their function.Cell 128:693-705
Kouzarides T, (2007) SnapShot: histone-modifying enzymes.Cell 128:802
Krogan NJ, Kim M, Tong A, Golshani A, Cagney G, Canadien V, Richards DP, Beattie BK, Emili A, Boone C, Shilatifard A, Buratowski S, Greenblatt J, (2003) Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II.Mol Cell Biol 23:4207-4218
Kuo AJ, Cheung P, Chen K, Zee BM, Kioi M, Lauring J, Xi Y, Park BH, Shi X, Garcia BA, Li W, Gozani O, (2011) NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming.Mol Cell 44:609-620
Lhoumaud P, Hennion M, Gamot A, Cuddapah S, Queille S, Liang J, Micas G, Morillon P, Urbach S, Bouchez O, Severac D, Emberly E, Zhao K, Cuvier O, (2014) Insulators recruit histone methyltransferase dMes4 to regulate chromatin of flanking genes.EMBO J 33:1599-1613
Li GM, (2013) Decoding the histone code: role of H3K36me3 in mismatch repair and implications for cancer susceptibility and therapy.Cancer Res 73:6379-6383
Li J, Moazed D, Gygi SP, (2002) Association of the histone methyltransferase Set2 with RNA polymerase II plays a role in transcription elongation.J Biol Chem 277:49383-49388
Li B, Howe L, Anderson S, Yates JR3rd, Workman JL, (2003) The Set2 histone methyltransferase functions through the phosphorylated carboxyl-terminal domain of RNA polymerase II.J Biol Chem 278:8897-8903
Li B, Gogol M, Carey M, Lee D, Seidel C, Workman JL, (2007) Combined action of PHD and chromo domains directs the Rpd3S HDAC to transcribed chromatin.Science 316:1050-1054
Li B, Jackson J, Simon MD, Fleharty B, Gogol M, Seidel C, Workman JL, Shilatifard A, (2009) Histone H3 lysine 36 dimethylation (H3K36me2) is sufficient to recruit the Rpd3s histone deacetylase complex and to repress spurious transcription.J Biol Chem 284:7970-7976
Li Y, Trojer P, Xu CF, Cheung P, Kuo A, Drury WJ3rd, Qiao Q, Neubert TA, Xu RM, Gozani O, Reinberg D, (2009) The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate.J Biol Chem 284:34283-34295
Lu C, Jain SU, Hoelper D, Bechet D, Molden RC, Ran L, Murphy D, Venneti S, Hameed M, Pawel BR, Wunder JS, Dickson BC, Lundgren SM, Jani KS, De Jay N, Papillon-Cavanagh S, Andrulis IL, Sawyer SL, Grynspan D, Turcotte RE, Nadaf J, Fahiminiyah S, Muir TW, Majewski J, Thompson CB, Chi P, Garcia BA, Allis CD, Jabado N, Lewis PW, (2016) Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape.Science 352:844-849
McDaniel SL, Strahl BD, (2017) Shaping the cellular landscape with Set2/SETD2 methylation.Cell Mol Life Sci 74:3317-3334
Miyazaki H, Higashimoto K, Yada Y, Endo TA, Sharif J, Komori T, Matsuda M, Koseki Y, Nakayama M, Soejima H, Handa H, Koseki H, Hirose S, Nishioka K, (2013) Ash1 l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract polycomb silencing.PLoS Genet 9:e1003897
Neri F, Rapelli S, Krepelova A, Incarnato D, Parlato C, Basile G, Maldotti M, Anselmi F, Oliviero S, (2017) Intragenic DNA methylation prevents spurious transcription initiation.Nature 543:72-77
Papp B, Muller J, (2006) Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins.Genes Dev 20:2041-2054
Popovic R, Martinez-Garcia E, Giannopoulou EG, Zhang Q, Zhang Q, Ezponda T, Shah MY, Zheng Y, Will CM, Small EC, Hua Y, Bulic M, Jiang Y, Carrara M, Calogero RA, Kath WL, Kelleher NL, Wang JP, Elemento O, Licht JD, (2014) Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation.PLoS Genet 10:e1004566
Qiao Q, Li Y, Chen Z, Wang M, Reinberg D, Xu RM, (2011) The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation.J Biol Chem 286:8361-8368
Ram O, Goren A, Amit I, Shoresh N, Yosef N, Ernst J, Kellis M, Gymrek M, Issner R, Coyne M, Durham T, Zhang X, Donaghey J, Epstein CB, Regev A, Bernstein BE, (2011) Combinatorial patterning of chromatin regulators uncovered by genome-wide location analysis in human cells.Cell 147:1628-1639
Rechtsteiner A, Ercan S, Takasaki T, Phippen TM, Egelhofer TA, Wang W, Kimura H, Lieb JD, Strome S, (2010) The histone H3K36 methyltransferase MES-4 acts epigenetically to transmit the memory of germline gene expression to progeny.PLoS Genet 6:e1001091
Ringrose L, Paro R, (2007) Polycomb/Trithorax response elements and epigenetic memory of cell identity.Development 134:223-232
Rogawski DS, Grembecka J, Cierpicki T, (2016) H3K36 methyltransferases as cancer drug targets: rationale and perspectives for inhibitor development.Fut Med Chem 8:1589-1607
Sankaran SM, Wilkinson AW, Elias JE, Gozani O, (2016) 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
Schmitges FW, Prusty AB, Faty M, Stutzer A, Lingaraju GM, Aiwazian J, Sack R, Hess D, Li L, Zhou S, Bunker RD, Wirth U, Bouwmeester T, Bauer A, Ly-Hartig N, Zhao K, Chan H, Gu J, Gut H, Fischle W, Müller J, Thomä NH, (2011) Histone methylation by PRC2 is inhibited by active chromatin marks.Mol Cell 42:330-341
Schwartz YB, Kahn TG, Stenberg P, Ohno K, Bourgon R, Pirrotta V, (2010) Alternative epigenetic chromatin states of polycomb target genes.PLoS Genet 6:e1000805
Shen C, Ipsaro JJ, Shi J, Milazzo JP, Wang E, Roe JS, Suzuki Y, Pappin DJ, Joshua-Tor L, Vakoc CR, (2015) NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler.Mol Cell 60:847-859
Srinivasan S, Dorighi KM, Tamkun JW, (2008) Drosophila Kismet regulates histone H3 lysine 27 methylation and early elongation by RNA polymerase II.PLoS Genet 4:e1000217
Strahl BD, Grant PA, Briggs SD, Sun ZW, Bone JR, Caldwell JA, Mollah S, Cook RG, Shabanowitz J, Hunt DF, Allis CD, (2002) Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression.Mol Cell Biol 22:1298-1306
Streubel G, Watson A, Jammula SG, Scelfo A, Fitzpatrick DJ, Oliviero G, McCole R, Conway E, Glancy E, Negri GL, Dillon E, Wynne K, Pasini D, Krogan NJ, Bracken AP, Cagney G, (2018) The H3K36me2 methyltransferase Nsd1 demarcates PRC2-mediated H3K27me2 and H3K27me3 domains in embryonic stem cells.Mol Cell 70:371-379
Tanaka Y, Katagiri Z, Kawahashi K, Kioussis D, Kitajima S, (2007) Trithorax-group protein ASH1 methylates histone H3 lysine 36.Gene 397:161-168
Venkatesh S, Workman JL, (2013) Set2 mediated H3 lysine 36 methylation: regulation of transcription elongation and implications in organismal development.Wiley Interdiscip Rev Dev Biol 2:685-700
Wagner EJ, Carpenter PB, (2012) Understanding the language of Lys36 methylation at histone H3.Nat Rev Mol Cell Biol 13:115-126
Wang Y, Niu Y, Li B, (2015) Balancing acts of SRI and an auto-inhibitory domain specify Set2 function at transcribed chromatin.Nucleic Acids Res 43:4881-4892
Wang C, Zhu B, Xiong J, (2018) Recruitment and reinforcement: maintaining epigenetic silencing.Sci China Life Sci 61:515-522
Wu H, Zeng H, Dong A, Li F, He H, Senisterra G, Seitova A, Duan S, Brown PJ, Vedadi M, Arrowsmith CH, Schapira M, (2013) Structure of the catalytic domain of EZH2 reveals conformational plasticity in cofactor and substrate binding sites and explains oncogenic mutations.PLoS ONE 8:e83737
Xiao T, Hall H, Kizer KO, Shibata Y, Hall MC, Borchers CH, Strahl BD, (2003) Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast.Genes Dev 17:654-663
Yang S, Zheng X, Lu C, Li GM, Allis CD, Li H, (2016) Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase.Genes Dev 30:1611-1616
Yuan W, Xie J, Long C, Erdjument-Bromage H, Ding X, Zheng Y, Tempst P, Chen S, Zhu B, Reinberg D, (2009) Heterogeneous nuclear ribonucleoprotein L Is a subunit of human KMT3a/Set2 complex required for H3 Lys-36 trimethylation activity in vivo.J Biol Chem 284:15701-15707
Yuan W, Xu M, Huang C, Liu N, Chen S, Zhu B, (2011) H3K36 methylation antagonizes PRC2-mediated H3K27 methylation.J Biol Chem 286:7983-7989
Yuan W, Wu T, Fu H, Dai C, Wu H, Liu N, Li X, Xu M, Zhang Z, Niu T, Han Z, Chai J, Zhou XJ, Gao S, Zhu B, (2012) Dense chromatin activates Polycomb repressive complex 2 to regulate H3 lysine 27 methylation.Science 337:971-975
Yuan G, Ma B, Yuan W, Zhang Z, Chen P, Ding X, Feng L, Shen X, Chen S, Li G, Zhu B, (2013) Histone H2A ubiquitination inhibits the enzymatic activity of H3 lysine 36 methyltransferases.J Biol Chem 288:30832-30842
Zheng W, Ibanez G, Wu H, Blum G, Zeng H, Dong A, Li F, Hajian T, Allali-Hassani A, Amaya MF, Siarheyeva A, Yu W, Brown PJ, Schapira M, Vedadi M, Min J, Luo M, (2012) Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2.J Am Chem Soc 134:18004-18014
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