1、Methylase Yeast(S.cerevisiae)Drosophila Mammals Substrate KMT1 H3K9 KMT2 KMT6 H3K27 H3K4 KMT4 H3K79 KMT3 H3K36 KMT5 H4K20 Biochemical/biological propertiesHeterochromatinformation/silencing G9a KMT1C Su(var)3-9KMT1A/B SUV39H1/2 KMT1A/B G9A GLP KMT1C/D CAF1 HP1 SETDB1 KMT1E SETDB1 ATF7IP ySet1/COMPAS
2、S Cps30 Cps60 Cps35 Set1 Cps25 Cps50 Cps40 Active transcription;homeotic gene expression;nuclearhormone receptorsignaling Wdr82 Wds Ash2 Cxxc1 Set1 Dpy30 Rbbp5 KMT2F/G Mnn1 WdsAsh2 Trx Dpy30 Rbbp5 KMT2A/B HcfPtipWds Ash2 Trr Dpy30 Rbbp5 UtxPa1 Lpt KMT2C/D WDR82 WDR5 ASH2 CXXC1 SET1A/B DPY30 RBBP5 KM
3、T2F/G MEN1 WDR5 ASH2 MLL1/2 DPY30 RBBP5 KMT2A/B HCF1 PTIP WDR5 ASH2 MLL3/4 DPY30 RBBP5 UTX PA1 NCOA6 KMT2C/D Drosophila COMPASS Family Mammalian COMPASS Family Active transcription Active transcription;cell-cycle regulation;Wnt signaling Transcriptionalrepression;DNAdamage response Polycomb silencin
4、g;X chromosomeinactivation;cellfate determination WHSC1 KMT3A KMT3A KMT3A KMT3B AF17 ENL TRRAP AF10 AF9 DOT1 Dot1Grappa KMT4 KMT4 KMT4 KMT5B/C SUV4-20H1/H2 KMT5B/C PR-Set7 KMT5A PR-Set7 KMT5A Pcl Jarid2 Jing Su(z)12 Esc/Escl Nurf55 E(z)MTF2 JARID2 AEBP2 SUZ12 EED RBBP4/RBBP7EZH1/EZH2PHF19 PHF1 KMT6
5、KMT6 DotCom Not detected CH3 CH3 CH3 Monomethylation(me)Dimethylation(me2)Trimethylation(me3)Not detected Not detected Mes-4 Set2 RNA Pol II CTD Set2 RNA Pol II CTD SET2 RNA Pol II CTD S-adenosyl-L-methionineKMT S-adenosyl-L-methionineKMT S-adenosyl-L-methionineKMT YeastS.cerevisiae)Su(var)3-9Not de
6、tected Su(var)4-20CH3 CH3 CH3 SnapShot:Histone LysineMethylase ComplexesMan Mohan,Hans-Martin Herz,and Ali ShilatifardStowers Institute for Medical Research,Kansas City,MO 64110,USA498 Cell 149,April 13,2012 2012 Elsevier Inc.DOI 10.1016/j.cell.2012.03.025See online version for legend and references
7、.498.e1 Cell 149,April 13,2012 2012 Elsevier Inc.DOI 10.1016/j.cell.2012.03.025SnapShot:Histone Lysine Methylase ComplexesMan Mohan,Hans-Martin Herz,and Ali ShilatifardStowers Institute for Medical Research,Kansas City,MO 64110,USALysine methyl transferases(KMTs)catalyze the transfer of one,two,or t
8、hree methyl groups from S-adenosyl-L-methionine(SAM)to the-amino group of a lysine residue on a histone to generate mono-,di-,and trimethylated histones.KMTs exist either singly or within complexes,in which the members of each complex modulate the activity of the enzymes.KMTs have been implicated in
9、 diverse roles in DNA-templated processes,and their mutations,deletions,or translocations have been linked with various human diseases.Known KMTs contain a SET domain(named after Drosophila Su(var)39,Enhancer of zeste E(z),and trithorax trx),with the exception of Dot1,shown in red,which harbors a un
10、ique catalytic domain.The first six characterized histone lysine methyltransferase families are discussed below.KMT1 FamilyThe KMT1 family is found in S.pombe(Clr4),plants,and metazoans,and includes Su(var)39 and G9a in Drosophila,and at least four enzymes in mammals:SUV39H1/2,G9a,GLP,and SETDB1.SUV
11、39H1/2 are responsible for generating the majority of histone 3 lysine 9(H3K9)trimethylation at pericentric heterochromatin,whereas G9a and GLP form functional heteromeric dimers in vivo to mono-and dimethylate H3K9 at euchromatic sites.SETDB1,which contains a methyl-CpG-binding domain,exists in a c
12、omplex with HP1 and CAF1,and this complex is believed to monomethylate histone H3.SETDB1,when in association with activating transcription factor 7 interacting protein(ATF7IP),becomes capable of H3K9 trimethylation and is associated with transcriptional repression.KMT2 FamilyThe KMT2 family can mono
13、-,di-and trimethylate histone H3K4.This family of enzymes is found within a macromolecular complex known as the COMPASS family and is highly conserved from yeast to human.The Set1/COMPASS in yeast was the first H3K4 methylase identified,with seven subunits in the complex,and is responsible for all m
14、ono-,di-,and trimethylation of H3K4 in yeast.In Drosophila,there are three COMPASS family members containing dSet1,Trx,and Trr.dSet1 is the major di-and trimethylase.Mammalian cells bear six COMPASS family members:dSet1 is represented by SET1A and SET1B,Trx is represented by MLL1 and MLL2(GeneID 975
15、7),and Trr is represented by MLL3 and MLL4(also known as ALR,GeneID 8085).All of the mammalian complexes share ASH2L,RBBP5,DPY30,HCF1,and WDR5.In addition to shared subunits,each COMPASS family member consists of complex specific subunits.SET1A and SET1B complexes uniquely associate with WDR82 and C
16、XXC1,MLL1/MLL2 complexes associate with Menin,and MLL3/4 complexes contain PTIP,PA1,UTX,and NCOA6.KMT3 FamilyThe KMT3 family methylates histone H3K36 and includes Set2,which is conserved from yeast to human.Set2 is known to associate with RNA Pol II during the elongation phase of transcription throu
17、gh interactions with Pol II C-terminal domain.Mammals also employ another family of enzymes represented by WHSC1(homologous to Drosophila Mes-4),WHSC1L1 and NSD2,each functioning in H3K36 dimethylation.Upregulation of WHSC1 is implicated in the development of multiple myeloma and other cancers.KMT4
18、FamilyDot1,which is the sole member of the family,is the only known non-SET domain-containing KMT,is conserved from yeast to humans,and methylates histone H3K79.Mammalian Dot1 exists in a large macromolecular complex known as DotCom,containing MLL-fusion proteins(AF10,ENL,AF9,and AF17),and is known
19、to have role in Wnt and JAK-STAT signaling and transcription.KMT5 FamilyThe KMT5 family methylates histone H4K20 and is characterized mainly in metozoans.Monomethylation is performed by a conserved enzyme,Pr-Set7,and is associated with various chromatin processes,including transcriptional activation
20、 and repression,DNA repair,cell-cycle progression,and DNA replication.Su(var)4-20 and its mammalian homologs SUV4-20H1/2 mediate di-and trimethylation of H4K20 and play a critical role in the maintenance of pericentric and telomeric heterochromatin.KMT6 FamilyThe KMT6 family methylates histone H3K27
21、 and is conserved from Drosophila to humans but does not exist in yeast.The KMT6 family is required to maintain transcriptional repression of many developmentally regulated genes,including homeotic genes,thereby promoting cell identity.Deregulation of certain members of the KMT6 complex has been lin
22、ked to various forms of cancer.In Drosophila,the catalytic subunit E(z)implements all mono-,di-,and trimethylation of H3K27.The two mammalian homologs of Droso-phila E(z)EZH1 and EZH2function redundantly to some degree and,in many cases,work in concert to achieve mono-,di-,and trimethylation of H3K2
23、7.Other core compo-nents of the complex are Su(z)12,Esc/Escl,and Nurf55 in Drosophila and SUZ12,EED,and RBBP4/7 in mammals.Accessory factors are also conserved between Drosophila(Jing,Pcl,and Jarid2)and mammals(AEBP2,PHF1,MTF2,PHF19,and JARID2).They either alter the enzymatic activity of the complex
24、 and/or are involved in recruitment of the core complex to certain KMT6 target genes.AbbreviationsAEBP2,AE-binding protein 2;AF17,ALL1-fused gene from chromosome 17;Ash2,absent,small,or homeotic discs 2;CAF1,chromatin assembly factor 1;COMPASS,complex proteins associated with Set1;Cps25,30,35,40,and
25、 60,compass subunit 25,30,40,40,and 60;CXXC1,CXXC finger protein 1;Dot1,disruptor of telomeric silencing 1;Dpy30,Dumpy-like 30;Wdr82,WD repeat domain 82;EED,embryonic ectoderm development;Esc,extra sexcombs;Escl,extra sexcombs-like;EZH1/2,enhancer of zeste homolog 1/2;HCF1,host cell factor 1;HP1,het
26、erochromatin protein 1;Jarid2,Jumonji,AT-rich interactive domain 2;MLL1/2/3/4,mixed lineage leukemia 1/2/3/4;MTF2,metal response element-binding transcription factor 2;Mnn1,Menin1;NCOA6,nuclear receptor coactivator 6;NURF55,nucleosome-remodeling factor 55;PHF1/19,PHD finger protein 1/19;PA1,PTIP-ass
27、ociated factor 1;Pcl,Polycomb-like;PTIP,PAX-interacting(with transcription activation domain)protein 1;Rbbp4/5/7,retinoblastoma-binding protein 4/5/7;SETDB1,SET domain,bifurcated 1;Su(var)39,suppressor of variegation 39;SUV39H1/2,suppressor of variegation 39 homolog 1/2;Su(z)12,suppressor of zeste 1
28、2;Trr,trithorax-related;TRRAP,transformation/transcription domain-associated protein;UTX,ubiquitously transcribed TPR protein on the X chromosome;Wdr5,WD repeat domain 5;Wds,will die slowly;WHSC1,Wolf-Hirschhorn syndrome candidate 1.AcknowledgmentsThe authors are grateful to Drs.Or Gozani and Edwin
29、Smith for their critical reading and valuable comments.Studies in the Shilatifard laboratory on chromatin-modifying machineries and childhood leukemia are supported by NIH grants R01CA150265,R01GM069905,and R01CA89455.RefeRencesBalakrishnan,L.,and Milavetz,B.(2010).Decoding the histone H4 lysine 20
30、methylation mark.Crit.Rev.Biochem.Mol.Biol.45,440452.Buratowski,S.,and Kim,T.(2010).The role of cotranscriptional histone methylations.Cold Spring Harb.Symp.Quant.Biol.75,95102.Fodor,B.D.,Shukeir,N.,Reuter,G.,and Jenuwein,T.(2010).Mammalian Su(var)genes in chromatin control.Annu.Rev.Cell Dev.Biol.26
31、,471501.Margueron,R.,and Reinberg,D.(2011).The Polycomb complex PRC2 and its mark in life.Nature 469,343349.Mohan,M.,Lin,C.,Guest,E.,and Shilatifard,A.(2010).Licensed to elongate:a molecular mechanism for MLL-based leukaemogenesis.Nat.Rev.Cancer 10,721728.Nguyen,A.T.,and Zhang,Y.(2011).The diverse functions of Dot1 and H3K79 methylation.Genes Dev.25,13451358.
