Full text data of SETDB1
SETDB1
(KIAA0067, KMT1E)
[Confidence: low (only semi-automatic identification from reviews)]
Histone-lysine N-methyltransferase SETDB1; 2.1.1.43 (ERG-associated protein with SET domain; ESET; Histone H3-K9 methyltransferase 4; H3-K9-HMTase 4; Lysine N-methyltransferase 1E; SET domain bifurcated 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Histone-lysine N-methyltransferase SETDB1; 2.1.1.43 (ERG-associated protein with SET domain; ESET; Histone H3-K9 methyltransferase 4; H3-K9-HMTase 4; Lysine N-methyltransferase 1E; SET domain bifurcated 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q15047
ID SETB1_HUMAN Reviewed; 1291 AA.
AC Q15047; A6NEW2; Q5SZD8; Q5SZD9; Q5SZE0; Q5SZE7; Q96GM9;
DT 15-NOV-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Histone-lysine N-methyltransferase SETDB1;
DE EC=2.1.1.43;
DE AltName: Full=ERG-associated protein with SET domain;
DE Short=ESET;
DE AltName: Full=Histone H3-K9 methyltransferase 4;
DE Short=H3-K9-HMTase 4;
DE AltName: Full=Lysine N-methyltransferase 1E;
DE AltName: Full=SET domain bifurcated 1;
GN Name=SETDB1; Synonyms=KIAA0067, KMT1E;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S.,
RA Seki N., Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II.
RT The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3), AND
RP VARIANT SER-506.
RC TISSUE=Muscle, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP CHARACTERIZATION, MUTAGENESIS OF 729-CYS--CYS-731; HIS-1224; CYS-1226
RP AND CYS-1279, AND INTERACTION WITH TRIM28.
RX PubMed=11959841; DOI=10.1101/gad.973302;
RA Schultz D.C., Ayyanathan K., Negorev D., Maul G.G., Rauscher F.J. III;
RT "SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific
RT methyltransferase that contributes to HP1-mediated silencing of
RT euchromatic genes by KRAB zinc-finger proteins.";
RL Genes Dev. 16:919-932(2002).
RN [6]
RP FUNCTION.
RX PubMed=12869583; DOI=10.1101/gad.1102803;
RA Ayyanathan K., Lechner M.S., Bell P., Maul G.G., Schultz D.C.,
RA Yamada Y., Tanaka K., Torigoe K., Rauscher F.J. III;
RT "Regulated recruitment of HP1 to a euchromatic gene induces
RT mitotically heritable, epigenetic gene silencing: a mammalian cell
RT culture model of gene variegation.";
RL Genes Dev. 17:1855-1869(2003).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, AND INTERACTION WITH
RP ATF7IP.
RX PubMed=14536086; DOI=10.1016/j.molcel.2003.08.007;
RA Wang H., An W., Cao R., Xia L., Erdjument-Bromage H., Chatton B.,
RA Tempst P., Roeder R.G., Zhang Y.;
RT "mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9
RT of histone H3 to cause transcriptional repression.";
RL Mol. Cell 12:475-487(2003).
RN [8]
RP FUNCTION, AND INTERACTION WITH MBD1 AND CHAF1A.
RX PubMed=15327775; DOI=10.1016/j.molcel.2004.06.043;
RA Sarraf S.A., Stancheva I.;
RT "Methyl-CpG binding protein MBD1 couples histone H3 methylation at
RT lysine 9 by SETDB1 to DNA replication and chromatin assembly.";
RL Mol. Cell 15:595-605(2004).
RN [9]
RP INTERACTION WITH CBX1 AND CBX5.
RX PubMed=15899859; DOI=10.1128/MCB.25.11.4552-4564.2005;
RA Verschure P.J., van der Kraan I., de Leeuw W., van der Vlag J.,
RA Carpenter A.E., Belmont A.S., van Driel R.;
RT "In vivo HP1 targeting causes large-scale chromatin condensation and
RT enhanced histone lysine methylation.";
RL Mol. Cell. Biol. 25:4552-4564(2005).
RN [10]
RP INTERACTION WITH MBD1.
RX PubMed=17066076; DOI=10.1038/sj.emboj.7601404;
RA Lyst M.J., Nan X., Stancheva I.;
RT "Regulation of MBD1-mediated transcriptional repression by SUMO and
RT PIAS proteins.";
RL EMBO J. 25:5317-5328(2006).
RN [11]
RP INTERACTION WITH ATF7IP AND ATF7IP2.
RX PubMed=15691849; DOI=10.1074/jbc.M413654200;
RA Ichimura T., Watanabe S., Sakamoto Y., Aoto T., Fujita N., Nakao M.;
RT "Transcriptional repression and heterochromatin formation by MBD1 and
RT MCAF/AM family proteins.";
RL J. Biol. Chem. 280:13928-13935(2005).
RN [12]
RP INTERACTION WITH DNMT3A AND DNMT3B.
RX PubMed=16682412; DOI=10.1074/jbc.M513249200;
RA Li H., Rauch T., Chen Z.-X., Szabo P.E., Riggs A.D., Pfeifer G.P.;
RT "The histone methyltransferase SETDB1 and the DNA methyltransferase
RT DNMT3A interact directly and localize to promoters silenced in cancer
RT cells.";
RL J. Biol. Chem. 281:19489-19500(2006).
RN [13]
RP INTERACTION WITH SUMO2.
RX PubMed=16567619; DOI=10.1073/pnas.0601066103;
RA Rosendorff A., Sakakibara S., Lu S., Kieff E., Xuan Y., DiBacco A.,
RA Shi Y., Shi Y., Gill G.;
RT "NXP-2 association with SUMO-2 depends on lysines required for
RT transcriptional repression.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:5308-5313(2006).
RN [14]
RP EXPRESSION IN HUNTINGTON DISEASE.
RX PubMed=17142323; DOI=10.1073/pnas.0606373103;
RA Ryu H., Lee J., Hagerty S.W., Soh B.Y., McAlpin S.E., Cormier K.A.,
RA Smith K.M., Ferrante R.J.;
RT "ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in
RT Huntington's disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:19176-19181(2006).
RN [15]
RP FUNCTION, INTERACTION WITH CHD7; NLK1 AND PPARG, PHOSPHORYLATION AT
RP THR-976, AND MUTAGENESIS OF THR-976.
RX PubMed=17952062; DOI=10.1038/ncb1647;
RA Takada I., Mihara M., Suzawa M., Ohtake F., Kobayashi S., Igarashi M.,
RA Youn M.Y., Takeyama K., Nakamura T., Mezaki Y., Takezawa S.,
RA Yogiashi Y., Kitagawa H., Yamada G., Takada S., Minami Y., Shibuya H.,
RA Matsumoto K., Kato S.;
RT "A histone lysine methyltransferase activated by non-canonical Wnt
RT signalling suppresses PPAR-gamma transactivation.";
RL Nat. Cell Biol. 9:1273-1285(2007).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1066, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [17]
RP IDENTIFICATION IN A COMPLEX WITH REST; CDYL; WIZ; EHMT1 AND EHMT2.
RX PubMed=19061646; DOI=10.1016/j.molcel.2008.10.025;
RA Mulligan P., Westbrook T.F., Ottinger M., Pavlova N., Chang B.,
RA Macia E., Shi Y.J., Barretina J., Liu J., Howley P.M., Elledge S.J.,
RA Shi Y.;
RT "CDYL bridges REST and histone methyltransferases for gene repression
RT and suppression of cellular transformation.";
RL Mol. Cell 32:718-726(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1066, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [19]
RP INTERACTION WITH MPHOSPH8.
RX PubMed=20871592; DOI=10.1038/emboj.2010.239;
RA Kokura K., Sun L., Bedford M.T., Fang J.;
RT "Methyl-H3K9-binding protein MPP8 mediates E-cadherin gene silencing
RT and promotes tumour cell motility and invasion.";
RL EMBO J. 29:3673-3687(2010).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1066, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.77 ANGSTROMS) OF 196-402.
RG Structural genomics consortium (SGC);
RT "The crystal structure of Tudor domain of human histone-lysine N-
RT methyltransferase SETDB1.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Histone methyltransferase that specifically
CC trimethylates 'Lys-9' of histone H3. H3 'Lys-9' trimethylation
CC represents a specific tag for epigenetic transcriptional
CC repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to
CC methylated histones. Mainly functions in euchromatin regions,
CC thereby playing a central role in the silencing of euchromatic
CC genes. H3 'Lys-9' trimethylation is coordinated with DNA
CC methylation. Probably forms a complex with MBD1 and ATF7IP that
CC represses transcription and couples DNA methylation and histone
CC 'Lys-9' trimethylation. Its activity is dependent on MBD1 and is
CC heritably maintained through DNA replication by being recruited by
CC CAF-1. SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor
CC recruited by KRAB zinc-finger proteins.
CC -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine + L-lysine-[histone] =
CC S-adenosyl-L-homocysteine + N(6)-methyl-L-lysine-[histone].
CC -!- SUBUNIT: Interacts with MBD1; interaction is abolished when MBD1
CC is sumoylated. Interacts with ATF7IP and ATF7IP2; the interaction
CC with ATF7IP is required to stimulate histone methyltransferase
CC activity and facilitate the conversion of dimethylated to
CC trimethylated H3 'Lys-9'. During DNA replication, it is recruited
CC by SETDB1 to form a S phase-specific complex that facilitates
CC methylation of H3 'Lys-9' during replication-coupled chromatin
CC assembly and is at least composed of the CAF-1 subunit CHAF1A,
CC MBD1 and SETDB1. Interacts with ERG, TRIM28/TIF1B, CBX1, CBX5,
CC CHD7, DNMT3A, HDAC1, HDAC2, NLK, PPARG, SIN3A, SIN3B, DNMT3B and
CC SUMO2. Interacts with MPHOSPH8. Part of a complex containing at
CC least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2.
CC -!- INTERACTION:
CC P31749:AKT1; NbExp=9; IntAct=EBI-79691, EBI-296087;
CC Q9Y6K1:DNMT3A; NbExp=7; IntAct=EBI-79691, EBI-923653;
CC Q9UIS9:MBD1; NbExp=3; IntAct=EBI-79691, EBI-867196;
CC Q99549:MPHOSPH8; NbExp=2; IntAct=EBI-79691, EBI-2653928;
CC -!- SUBCELLULAR LOCATION: Nucleus. Chromosome. Note=Associated with
CC non-pericentromeric regions of chromatin. Excluded from nucleoli
CC and islands of condensed chromatin.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q15047-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q15047-2; Sequence=VSP_002217, VSP_002218;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q15047-3; Sequence=VSP_034600;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. High expression in testis.
CC -!- DOMAIN: The pre-SET, SET and post-SET domains are all required for
CC methyltransferase activity. The 347-amino-acid insertion in the
CC SET domain has no effect on the catalytic activity.
CC -!- DOMAIN: Isoform 2 lacks all domains required for histone
CC methyltransferase activity.
CC -!- MISCELLANEOUS: Highly up-regulated in Huntington disease patients,
CC suggesting that participates in the altered chromatin modulation
CC and transcription dysfunction observed in Huntington disease. Its
CC down-regulation has salubrious effects on patients, suggesting
CC that it may be a promising treatment in Huntington disease
CC patients.
CC -!- SIMILARITY: Belongs to the class V-like SAM-binding
CC methyltransferase superfamily. Histone-lysine methyltransferase
CC family. Suvar3-9 subfamily.
CC -!- SIMILARITY: Contains 1 MBD (methyl-CpG-binding) domain.
CC -!- SIMILARITY: Contains 1 post-SET domain.
CC -!- SIMILARITY: Contains 1 pre-SET domain.
CC -!- SIMILARITY: Contains 1 SET domain.
CC -!- SIMILARITY: Contains 2 Tudor domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA06689.2; Type=Erroneous initiation;
CC Sequence=CAI13325.1; Type=Erroneous gene model prediction;
CC Sequence=CAI13326.1; Type=Erroneous gene model prediction;
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DR EMBL; D31891; BAA06689.2; ALT_INIT; mRNA.
DR EMBL; AL590133; CAI13325.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL590133; CAI13326.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL590133; CAI13327.1; -; Genomic_DNA.
DR EMBL; AL590133; CAI13328.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53506.1; -; Genomic_DNA.
DR EMBL; BC009362; AAH09362.1; -; mRNA.
DR EMBL; BC028671; AAH28671.1; -; mRNA.
DR RefSeq; NP_001138887.1; NM_001145415.1.
DR RefSeq; NP_001230420.1; NM_001243491.1.
DR RefSeq; NP_036564.3; NM_012432.3.
DR UniGene; Hs.643565; -.
DR PDB; 3DLM; X-ray; 1.77 A; A=196-402.
DR PDBsum; 3DLM; -.
DR ProteinModelPortal; Q15047; -.
DR SMR; Q15047; 196-397, 681-881, 1165-1290.
DR DIP; DIP-31029N; -.
DR IntAct; Q15047; 98.
DR MINT; MINT-1184137; -.
DR STRING; 9606.ENSP00000357965; -.
DR ChEMBL; CHEMBL2321646; -.
DR PhosphoSite; Q15047; -.
DR DMDM; 25091210; -.
DR PaxDb; Q15047; -.
DR PRIDE; Q15047; -.
DR Ensembl; ENST00000271640; ENSP00000271640; ENSG00000143379.
DR Ensembl; ENST00000368962; ENSP00000357958; ENSG00000143379.
DR Ensembl; ENST00000368969; ENSP00000357965; ENSG00000143379.
DR GeneID; 9869; -.
DR KEGG; hsa:9869; -.
DR UCSC; uc001evu.2; human.
DR CTD; 9869; -.
DR GeneCards; GC01P150898; -.
DR HGNC; HGNC:10761; SETDB1.
DR HPA; HPA018142; -.
DR MIM; 604396; gene.
DR neXtProt; NX_Q15047; -.
DR PharmGKB; PA35679; -.
DR eggNOG; COG2940; -.
DR HOVERGEN; HBG061013; -.
DR InParanoid; Q15047; -.
DR KO; K11421; -.
DR OMA; GSVGSGH; -.
DR OrthoDB; EOG7ZD1TG; -.
DR ChiTaRS; SETDB1; human.
DR EvolutionaryTrace; Q15047; -.
DR GeneWiki; SETDB1; -.
DR GenomeRNAi; 9869; -.
DR NextBio; 37203; -.
DR PRO; PR:Q15047; -.
DR ArrayExpress; Q15047; -.
DR Bgee; Q15047; -.
DR CleanEx; HS_SETDB1; -.
DR Genevestigator; Q15047; -.
DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0003677; F:DNA binding; IEA:InterPro.
DR GO; GO:0018024; F:histone-lysine N-methyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0060348; P:bone development; IEA:Ensembl.
DR GO; GO:0001833; P:inner cell mass cell proliferation; IEA:Ensembl.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR InterPro; IPR016177; DNA-bd_dom.
DR InterPro; IPR025796; Hist-Lys_N-MeTrfase_SETDB1.
DR InterPro; IPR001739; Methyl_CpG_DNA-bd.
DR InterPro; IPR003616; Post-SET_dom.
DR InterPro; IPR007728; Pre-SET_dom.
DR InterPro; IPR003606; Pre-SET_Zn-bd_sub.
DR InterPro; IPR001214; SET_dom.
DR InterPro; IPR002999; Tudor.
DR Pfam; PF01429; MBD; 1.
DR Pfam; PF05033; Pre-SET; 1.
DR Pfam; PF00856; SET; 1.
DR SMART; SM00391; MBD; 1.
DR SMART; SM00508; PostSET; 1.
DR SMART; SM00468; PreSET; 1.
DR SMART; SM00317; SET; 1.
DR SMART; SM00333; TUDOR; 2.
DR SUPFAM; SSF54171; SSF54171; 1.
DR PROSITE; PS50982; MBD; 1.
DR PROSITE; PS50868; POST_SET; 1.
DR PROSITE; PS50867; PRE_SET; 1.
DR PROSITE; PS51573; SAM_MT43_SUVAR39_1; 1.
DR PROSITE; PS50280; SET; 1.
DR PROSITE; PS50304; TUDOR; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Chromatin regulator; Chromosome;
KW Coiled coil; Complete proteome; Isopeptide bond; Methyltransferase;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Repressor; S-adenosyl-L-methionine; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation.
FT CHAIN 1 1291 Histone-lysine N-methyltransferase
FT SETDB1.
FT /FTId=PRO_0000186064.
FT DOMAIN 257 320 Tudor 1.
FT DOMAIN 347 403 Tudor 2.
FT DOMAIN 594 665 MBD.
FT DOMAIN 727 800 Pre-SET.
FT DOMAIN 803 1266 SET.
FT DOMAIN 1275 1291 Post-SET.
FT COILED 18 64 Potential.
FT MOD_RES 976 976 Phosphothreonine; by NLK (Probable).
FT MOD_RES 1066 1066 Phosphoserine.
FT CROSSLNK 182 182 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 381 397 DDKRCEWIYRGSTRLEP -> VLFFSTILEAEVGGGGT
FT (in isoform 2).
FT /FTId=VSP_002217.
FT VAR_SEQ 398 1291 Missing (in isoform 2).
FT /FTId=VSP_002218.
FT VAR_SEQ 1254 1254 Missing (in isoform 3).
FT /FTId=VSP_034600.
FT VARIANT 236 236 N -> S (in dbSNP:rs2271075).
FT /FTId=VAR_014284.
FT VARIANT 506 506 P -> S (in dbSNP:rs17852587).
FT /FTId=VAR_031281.
FT VARIANT 824 824 A -> G (in dbSNP:rs2691551).
FT /FTId=VAR_014286.
FT VARIANT 824 824 A -> P (in dbSNP:rs2814054).
FT /FTId=VAR_014285.
FT MUTAGEN 729 731 CDC->LDP: Abolishes methyltransferase
FT activity.
FT MUTAGEN 976 976 T->A: Abrogates interaction with CHD7,
FT NLK and PPARG. Reduces phosphorylation by
FT NLK. Reduces transcriptional repression.
FT MUTAGEN 1224 1224 H->K: Abolishes methyltransferase
FT activity.
FT MUTAGEN 1226 1226 C->A: Abolishes methyltransferase
FT activity.
FT MUTAGEN 1279 1279 C->Y: Abolishes methyltransferase
FT activity.
FT STRAND 203 207
FT STRAND 213 224
FT STRAND 227 237
FT STRAND 239 242
FT HELIX 244 246
FT STRAND 247 251
FT HELIX 255 257
FT STRAND 263 269
FT STRAND 274 283
FT TURN 287 290
FT STRAND 293 297
FT STRAND 302 305
FT HELIX 307 309
FT STRAND 310 315
FT HELIX 320 323
FT HELIX 327 339
FT STRAND 353 358
FT STRAND 361 371
FT STRAND 374 379
FT TURN 380 383
FT STRAND 384 389
SQ SEQUENCE 1291 AA; 143157 MW; D8841B4C41B911C5 CRC64;
MSSLPGCIGL DAATATVESE EIAELQQAVV EELGISMEEL RHFIDEELEK MDCVQQRKKQ
LAELETWVIQ KESEVAHVDQ LFDDASRAVT NCESLVKDFY SKLGLQYRDS SSEDESSRPT
EIIEIPDEDD DVLSIDSGDA GSRTPKDQKL REAMAALRKS AQDVQKFMDA VNKKSSSQDL
HKGTLSQMSG ELSKDGDLIV SMRILGKKRT KTWHKGTLIA IQTVGPGKKY KVKFDNKGKS
LLSGNHIAYD YHPPADKLYV GSRVVAKYKD GNQVWLYAGI VAETPNVKNK LRFLIFFDDG
YASYVTQSEL YPICRPLKKT WEDIEDISCR DFIEEYVTAY PNRPMVLLKS GQLIKTEWEG
TWWKSRVEEV DGSLVRILFL DDKRCEWIYR GSTRLEPMFS MKTSSASALE KKQGQLRTRP
NMGAVRSKGP VVQYTQDLTG TGTQFKPVEP PQPTAPPAPP FPPAPPLSPQ AGDSDLESQL
AQSRKQVAKK STSFRPGSVG SGHSSPTSPA LSENVSGGKP GINQTYRSPL GSTASAPAPS
ALPAPPAPPV FHGMLERAPA EPSYRAPMEK LFYLPHVCSY TCLSRVRPMR NEQYRGKNPL
LVPLLYDFRR MTARRRVNRK MGFHVIYKTP CGLCLRTMQE IERYLFETGC DFLFLEMFCL
DPYVLVDRKF QPYKPFYYIL DITYGKEDVP LSCVNEIDTT PPPQVAYSKE RIPGKGVFIN
TGPEFLVGCD CKDGCRDKSK CACHQLTIQA TACTPGGQIN PNSGYQYKRL EECLPTGVYE
CNKRCKCDPN MCTNRLVQHG LQVRLQLFKT QNKGWGIRCL DDIAKGSFVC IYAGKILTDD
FADKEGLEMG DEYFANLDHI ESVENFKEGY ESDAPCSSDS SGVDLKDQED GNSGTEDPEE
SNDDSSDDNF CKDEDFSTSS VWRSYATRRQ TRGQKENGLS ETTSKDSHPP DLGPPHIPVP
PSIPVGGCNP PSSEETPKNK VASWLSCNSV SEGGFADSDS HSSFKTNEGG EGRAGGSRME
AEKASTSGLG IKDEGDIKQA KKEDTDDRNK MSVVTESSRN YGYNPSPVKP EGLRRPPSKT
SMHQSRRLMA SAQSNPDDVL TLSSSTESEG ESGTSRKPTA GQTSATAVDS DDIQTISSGS
EGDDFEDKKN MTGPMKRQVA VKSTRGFALK STHGIAIKST NMASVDKGES APVRKNTRQF
YDGEESCYII DAKLEGNLGR YLNHSCSPNL FVQNVFVDTH DLRFPWVAFF ASKRIRAGTE
LTWDYNYEVG SVEGKELLCC CGAIECRGRL L
//
ID SETB1_HUMAN Reviewed; 1291 AA.
AC Q15047; A6NEW2; Q5SZD8; Q5SZD9; Q5SZE0; Q5SZE7; Q96GM9;
DT 15-NOV-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Histone-lysine N-methyltransferase SETDB1;
DE EC=2.1.1.43;
DE AltName: Full=ERG-associated protein with SET domain;
DE Short=ESET;
DE AltName: Full=Histone H3-K9 methyltransferase 4;
DE Short=H3-K9-HMTase 4;
DE AltName: Full=Lysine N-methyltransferase 1E;
DE AltName: Full=SET domain bifurcated 1;
GN Name=SETDB1; Synonyms=KIAA0067, KMT1E;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S.,
RA Seki N., Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II.
RT The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3), AND
RP VARIANT SER-506.
RC TISSUE=Muscle, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP CHARACTERIZATION, MUTAGENESIS OF 729-CYS--CYS-731; HIS-1224; CYS-1226
RP AND CYS-1279, AND INTERACTION WITH TRIM28.
RX PubMed=11959841; DOI=10.1101/gad.973302;
RA Schultz D.C., Ayyanathan K., Negorev D., Maul G.G., Rauscher F.J. III;
RT "SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific
RT methyltransferase that contributes to HP1-mediated silencing of
RT euchromatic genes by KRAB zinc-finger proteins.";
RL Genes Dev. 16:919-932(2002).
RN [6]
RP FUNCTION.
RX PubMed=12869583; DOI=10.1101/gad.1102803;
RA Ayyanathan K., Lechner M.S., Bell P., Maul G.G., Schultz D.C.,
RA Yamada Y., Tanaka K., Torigoe K., Rauscher F.J. III;
RT "Regulated recruitment of HP1 to a euchromatic gene induces
RT mitotically heritable, epigenetic gene silencing: a mammalian cell
RT culture model of gene variegation.";
RL Genes Dev. 17:1855-1869(2003).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, AND INTERACTION WITH
RP ATF7IP.
RX PubMed=14536086; DOI=10.1016/j.molcel.2003.08.007;
RA Wang H., An W., Cao R., Xia L., Erdjument-Bromage H., Chatton B.,
RA Tempst P., Roeder R.G., Zhang Y.;
RT "mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9
RT of histone H3 to cause transcriptional repression.";
RL Mol. Cell 12:475-487(2003).
RN [8]
RP FUNCTION, AND INTERACTION WITH MBD1 AND CHAF1A.
RX PubMed=15327775; DOI=10.1016/j.molcel.2004.06.043;
RA Sarraf S.A., Stancheva I.;
RT "Methyl-CpG binding protein MBD1 couples histone H3 methylation at
RT lysine 9 by SETDB1 to DNA replication and chromatin assembly.";
RL Mol. Cell 15:595-605(2004).
RN [9]
RP INTERACTION WITH CBX1 AND CBX5.
RX PubMed=15899859; DOI=10.1128/MCB.25.11.4552-4564.2005;
RA Verschure P.J., van der Kraan I., de Leeuw W., van der Vlag J.,
RA Carpenter A.E., Belmont A.S., van Driel R.;
RT "In vivo HP1 targeting causes large-scale chromatin condensation and
RT enhanced histone lysine methylation.";
RL Mol. Cell. Biol. 25:4552-4564(2005).
RN [10]
RP INTERACTION WITH MBD1.
RX PubMed=17066076; DOI=10.1038/sj.emboj.7601404;
RA Lyst M.J., Nan X., Stancheva I.;
RT "Regulation of MBD1-mediated transcriptional repression by SUMO and
RT PIAS proteins.";
RL EMBO J. 25:5317-5328(2006).
RN [11]
RP INTERACTION WITH ATF7IP AND ATF7IP2.
RX PubMed=15691849; DOI=10.1074/jbc.M413654200;
RA Ichimura T., Watanabe S., Sakamoto Y., Aoto T., Fujita N., Nakao M.;
RT "Transcriptional repression and heterochromatin formation by MBD1 and
RT MCAF/AM family proteins.";
RL J. Biol. Chem. 280:13928-13935(2005).
RN [12]
RP INTERACTION WITH DNMT3A AND DNMT3B.
RX PubMed=16682412; DOI=10.1074/jbc.M513249200;
RA Li H., Rauch T., Chen Z.-X., Szabo P.E., Riggs A.D., Pfeifer G.P.;
RT "The histone methyltransferase SETDB1 and the DNA methyltransferase
RT DNMT3A interact directly and localize to promoters silenced in cancer
RT cells.";
RL J. Biol. Chem. 281:19489-19500(2006).
RN [13]
RP INTERACTION WITH SUMO2.
RX PubMed=16567619; DOI=10.1073/pnas.0601066103;
RA Rosendorff A., Sakakibara S., Lu S., Kieff E., Xuan Y., DiBacco A.,
RA Shi Y., Shi Y., Gill G.;
RT "NXP-2 association with SUMO-2 depends on lysines required for
RT transcriptional repression.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:5308-5313(2006).
RN [14]
RP EXPRESSION IN HUNTINGTON DISEASE.
RX PubMed=17142323; DOI=10.1073/pnas.0606373103;
RA Ryu H., Lee J., Hagerty S.W., Soh B.Y., McAlpin S.E., Cormier K.A.,
RA Smith K.M., Ferrante R.J.;
RT "ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in
RT Huntington's disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:19176-19181(2006).
RN [15]
RP FUNCTION, INTERACTION WITH CHD7; NLK1 AND PPARG, PHOSPHORYLATION AT
RP THR-976, AND MUTAGENESIS OF THR-976.
RX PubMed=17952062; DOI=10.1038/ncb1647;
RA Takada I., Mihara M., Suzawa M., Ohtake F., Kobayashi S., Igarashi M.,
RA Youn M.Y., Takeyama K., Nakamura T., Mezaki Y., Takezawa S.,
RA Yogiashi Y., Kitagawa H., Yamada G., Takada S., Minami Y., Shibuya H.,
RA Matsumoto K., Kato S.;
RT "A histone lysine methyltransferase activated by non-canonical Wnt
RT signalling suppresses PPAR-gamma transactivation.";
RL Nat. Cell Biol. 9:1273-1285(2007).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1066, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [17]
RP IDENTIFICATION IN A COMPLEX WITH REST; CDYL; WIZ; EHMT1 AND EHMT2.
RX PubMed=19061646; DOI=10.1016/j.molcel.2008.10.025;
RA Mulligan P., Westbrook T.F., Ottinger M., Pavlova N., Chang B.,
RA Macia E., Shi Y.J., Barretina J., Liu J., Howley P.M., Elledge S.J.,
RA Shi Y.;
RT "CDYL bridges REST and histone methyltransferases for gene repression
RT and suppression of cellular transformation.";
RL Mol. Cell 32:718-726(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1066, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [19]
RP INTERACTION WITH MPHOSPH8.
RX PubMed=20871592; DOI=10.1038/emboj.2010.239;
RA Kokura K., Sun L., Bedford M.T., Fang J.;
RT "Methyl-H3K9-binding protein MPP8 mediates E-cadherin gene silencing
RT and promotes tumour cell motility and invasion.";
RL EMBO J. 29:3673-3687(2010).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1066, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.77 ANGSTROMS) OF 196-402.
RG Structural genomics consortium (SGC);
RT "The crystal structure of Tudor domain of human histone-lysine N-
RT methyltransferase SETDB1.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Histone methyltransferase that specifically
CC trimethylates 'Lys-9' of histone H3. H3 'Lys-9' trimethylation
CC represents a specific tag for epigenetic transcriptional
CC repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to
CC methylated histones. Mainly functions in euchromatin regions,
CC thereby playing a central role in the silencing of euchromatic
CC genes. H3 'Lys-9' trimethylation is coordinated with DNA
CC methylation. Probably forms a complex with MBD1 and ATF7IP that
CC represses transcription and couples DNA methylation and histone
CC 'Lys-9' trimethylation. Its activity is dependent on MBD1 and is
CC heritably maintained through DNA replication by being recruited by
CC CAF-1. SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor
CC recruited by KRAB zinc-finger proteins.
CC -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine + L-lysine-[histone] =
CC S-adenosyl-L-homocysteine + N(6)-methyl-L-lysine-[histone].
CC -!- SUBUNIT: Interacts with MBD1; interaction is abolished when MBD1
CC is sumoylated. Interacts with ATF7IP and ATF7IP2; the interaction
CC with ATF7IP is required to stimulate histone methyltransferase
CC activity and facilitate the conversion of dimethylated to
CC trimethylated H3 'Lys-9'. During DNA replication, it is recruited
CC by SETDB1 to form a S phase-specific complex that facilitates
CC methylation of H3 'Lys-9' during replication-coupled chromatin
CC assembly and is at least composed of the CAF-1 subunit CHAF1A,
CC MBD1 and SETDB1. Interacts with ERG, TRIM28/TIF1B, CBX1, CBX5,
CC CHD7, DNMT3A, HDAC1, HDAC2, NLK, PPARG, SIN3A, SIN3B, DNMT3B and
CC SUMO2. Interacts with MPHOSPH8. Part of a complex containing at
CC least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2.
CC -!- INTERACTION:
CC P31749:AKT1; NbExp=9; IntAct=EBI-79691, EBI-296087;
CC Q9Y6K1:DNMT3A; NbExp=7; IntAct=EBI-79691, EBI-923653;
CC Q9UIS9:MBD1; NbExp=3; IntAct=EBI-79691, EBI-867196;
CC Q99549:MPHOSPH8; NbExp=2; IntAct=EBI-79691, EBI-2653928;
CC -!- SUBCELLULAR LOCATION: Nucleus. Chromosome. Note=Associated with
CC non-pericentromeric regions of chromatin. Excluded from nucleoli
CC and islands of condensed chromatin.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q15047-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q15047-2; Sequence=VSP_002217, VSP_002218;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q15047-3; Sequence=VSP_034600;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. High expression in testis.
CC -!- DOMAIN: The pre-SET, SET and post-SET domains are all required for
CC methyltransferase activity. The 347-amino-acid insertion in the
CC SET domain has no effect on the catalytic activity.
CC -!- DOMAIN: Isoform 2 lacks all domains required for histone
CC methyltransferase activity.
CC -!- MISCELLANEOUS: Highly up-regulated in Huntington disease patients,
CC suggesting that participates in the altered chromatin modulation
CC and transcription dysfunction observed in Huntington disease. Its
CC down-regulation has salubrious effects on patients, suggesting
CC that it may be a promising treatment in Huntington disease
CC patients.
CC -!- SIMILARITY: Belongs to the class V-like SAM-binding
CC methyltransferase superfamily. Histone-lysine methyltransferase
CC family. Suvar3-9 subfamily.
CC -!- SIMILARITY: Contains 1 MBD (methyl-CpG-binding) domain.
CC -!- SIMILARITY: Contains 1 post-SET domain.
CC -!- SIMILARITY: Contains 1 pre-SET domain.
CC -!- SIMILARITY: Contains 1 SET domain.
CC -!- SIMILARITY: Contains 2 Tudor domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA06689.2; Type=Erroneous initiation;
CC Sequence=CAI13325.1; Type=Erroneous gene model prediction;
CC Sequence=CAI13326.1; Type=Erroneous gene model prediction;
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DR EMBL; D31891; BAA06689.2; ALT_INIT; mRNA.
DR EMBL; AL590133; CAI13325.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL590133; CAI13326.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL590133; CAI13327.1; -; Genomic_DNA.
DR EMBL; AL590133; CAI13328.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53506.1; -; Genomic_DNA.
DR EMBL; BC009362; AAH09362.1; -; mRNA.
DR EMBL; BC028671; AAH28671.1; -; mRNA.
DR RefSeq; NP_001138887.1; NM_001145415.1.
DR RefSeq; NP_001230420.1; NM_001243491.1.
DR RefSeq; NP_036564.3; NM_012432.3.
DR UniGene; Hs.643565; -.
DR PDB; 3DLM; X-ray; 1.77 A; A=196-402.
DR PDBsum; 3DLM; -.
DR ProteinModelPortal; Q15047; -.
DR SMR; Q15047; 196-397, 681-881, 1165-1290.
DR DIP; DIP-31029N; -.
DR IntAct; Q15047; 98.
DR MINT; MINT-1184137; -.
DR STRING; 9606.ENSP00000357965; -.
DR ChEMBL; CHEMBL2321646; -.
DR PhosphoSite; Q15047; -.
DR DMDM; 25091210; -.
DR PaxDb; Q15047; -.
DR PRIDE; Q15047; -.
DR Ensembl; ENST00000271640; ENSP00000271640; ENSG00000143379.
DR Ensembl; ENST00000368962; ENSP00000357958; ENSG00000143379.
DR Ensembl; ENST00000368969; ENSP00000357965; ENSG00000143379.
DR GeneID; 9869; -.
DR KEGG; hsa:9869; -.
DR UCSC; uc001evu.2; human.
DR CTD; 9869; -.
DR GeneCards; GC01P150898; -.
DR HGNC; HGNC:10761; SETDB1.
DR HPA; HPA018142; -.
DR MIM; 604396; gene.
DR neXtProt; NX_Q15047; -.
DR PharmGKB; PA35679; -.
DR eggNOG; COG2940; -.
DR HOVERGEN; HBG061013; -.
DR InParanoid; Q15047; -.
DR KO; K11421; -.
DR OMA; GSVGSGH; -.
DR OrthoDB; EOG7ZD1TG; -.
DR ChiTaRS; SETDB1; human.
DR EvolutionaryTrace; Q15047; -.
DR GeneWiki; SETDB1; -.
DR GenomeRNAi; 9869; -.
DR NextBio; 37203; -.
DR PRO; PR:Q15047; -.
DR ArrayExpress; Q15047; -.
DR Bgee; Q15047; -.
DR CleanEx; HS_SETDB1; -.
DR Genevestigator; Q15047; -.
DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0003677; F:DNA binding; IEA:InterPro.
DR GO; GO:0018024; F:histone-lysine N-methyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0060348; P:bone development; IEA:Ensembl.
DR GO; GO:0001833; P:inner cell mass cell proliferation; IEA:Ensembl.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR InterPro; IPR016177; DNA-bd_dom.
DR InterPro; IPR025796; Hist-Lys_N-MeTrfase_SETDB1.
DR InterPro; IPR001739; Methyl_CpG_DNA-bd.
DR InterPro; IPR003616; Post-SET_dom.
DR InterPro; IPR007728; Pre-SET_dom.
DR InterPro; IPR003606; Pre-SET_Zn-bd_sub.
DR InterPro; IPR001214; SET_dom.
DR InterPro; IPR002999; Tudor.
DR Pfam; PF01429; MBD; 1.
DR Pfam; PF05033; Pre-SET; 1.
DR Pfam; PF00856; SET; 1.
DR SMART; SM00391; MBD; 1.
DR SMART; SM00508; PostSET; 1.
DR SMART; SM00468; PreSET; 1.
DR SMART; SM00317; SET; 1.
DR SMART; SM00333; TUDOR; 2.
DR SUPFAM; SSF54171; SSF54171; 1.
DR PROSITE; PS50982; MBD; 1.
DR PROSITE; PS50868; POST_SET; 1.
DR PROSITE; PS50867; PRE_SET; 1.
DR PROSITE; PS51573; SAM_MT43_SUVAR39_1; 1.
DR PROSITE; PS50280; SET; 1.
DR PROSITE; PS50304; TUDOR; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Chromatin regulator; Chromosome;
KW Coiled coil; Complete proteome; Isopeptide bond; Methyltransferase;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Repressor; S-adenosyl-L-methionine; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation.
FT CHAIN 1 1291 Histone-lysine N-methyltransferase
FT SETDB1.
FT /FTId=PRO_0000186064.
FT DOMAIN 257 320 Tudor 1.
FT DOMAIN 347 403 Tudor 2.
FT DOMAIN 594 665 MBD.
FT DOMAIN 727 800 Pre-SET.
FT DOMAIN 803 1266 SET.
FT DOMAIN 1275 1291 Post-SET.
FT COILED 18 64 Potential.
FT MOD_RES 976 976 Phosphothreonine; by NLK (Probable).
FT MOD_RES 1066 1066 Phosphoserine.
FT CROSSLNK 182 182 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 381 397 DDKRCEWIYRGSTRLEP -> VLFFSTILEAEVGGGGT
FT (in isoform 2).
FT /FTId=VSP_002217.
FT VAR_SEQ 398 1291 Missing (in isoform 2).
FT /FTId=VSP_002218.
FT VAR_SEQ 1254 1254 Missing (in isoform 3).
FT /FTId=VSP_034600.
FT VARIANT 236 236 N -> S (in dbSNP:rs2271075).
FT /FTId=VAR_014284.
FT VARIANT 506 506 P -> S (in dbSNP:rs17852587).
FT /FTId=VAR_031281.
FT VARIANT 824 824 A -> G (in dbSNP:rs2691551).
FT /FTId=VAR_014286.
FT VARIANT 824 824 A -> P (in dbSNP:rs2814054).
FT /FTId=VAR_014285.
FT MUTAGEN 729 731 CDC->LDP: Abolishes methyltransferase
FT activity.
FT MUTAGEN 976 976 T->A: Abrogates interaction with CHD7,
FT NLK and PPARG. Reduces phosphorylation by
FT NLK. Reduces transcriptional repression.
FT MUTAGEN 1224 1224 H->K: Abolishes methyltransferase
FT activity.
FT MUTAGEN 1226 1226 C->A: Abolishes methyltransferase
FT activity.
FT MUTAGEN 1279 1279 C->Y: Abolishes methyltransferase
FT activity.
FT STRAND 203 207
FT STRAND 213 224
FT STRAND 227 237
FT STRAND 239 242
FT HELIX 244 246
FT STRAND 247 251
FT HELIX 255 257
FT STRAND 263 269
FT STRAND 274 283
FT TURN 287 290
FT STRAND 293 297
FT STRAND 302 305
FT HELIX 307 309
FT STRAND 310 315
FT HELIX 320 323
FT HELIX 327 339
FT STRAND 353 358
FT STRAND 361 371
FT STRAND 374 379
FT TURN 380 383
FT STRAND 384 389
SQ SEQUENCE 1291 AA; 143157 MW; D8841B4C41B911C5 CRC64;
MSSLPGCIGL DAATATVESE EIAELQQAVV EELGISMEEL RHFIDEELEK MDCVQQRKKQ
LAELETWVIQ KESEVAHVDQ LFDDASRAVT NCESLVKDFY SKLGLQYRDS SSEDESSRPT
EIIEIPDEDD DVLSIDSGDA GSRTPKDQKL REAMAALRKS AQDVQKFMDA VNKKSSSQDL
HKGTLSQMSG ELSKDGDLIV SMRILGKKRT KTWHKGTLIA IQTVGPGKKY KVKFDNKGKS
LLSGNHIAYD YHPPADKLYV GSRVVAKYKD GNQVWLYAGI VAETPNVKNK LRFLIFFDDG
YASYVTQSEL YPICRPLKKT WEDIEDISCR DFIEEYVTAY PNRPMVLLKS GQLIKTEWEG
TWWKSRVEEV DGSLVRILFL DDKRCEWIYR GSTRLEPMFS MKTSSASALE KKQGQLRTRP
NMGAVRSKGP VVQYTQDLTG TGTQFKPVEP PQPTAPPAPP FPPAPPLSPQ AGDSDLESQL
AQSRKQVAKK STSFRPGSVG SGHSSPTSPA LSENVSGGKP GINQTYRSPL GSTASAPAPS
ALPAPPAPPV FHGMLERAPA EPSYRAPMEK LFYLPHVCSY TCLSRVRPMR NEQYRGKNPL
LVPLLYDFRR MTARRRVNRK MGFHVIYKTP CGLCLRTMQE IERYLFETGC DFLFLEMFCL
DPYVLVDRKF QPYKPFYYIL DITYGKEDVP LSCVNEIDTT PPPQVAYSKE RIPGKGVFIN
TGPEFLVGCD CKDGCRDKSK CACHQLTIQA TACTPGGQIN PNSGYQYKRL EECLPTGVYE
CNKRCKCDPN MCTNRLVQHG LQVRLQLFKT QNKGWGIRCL DDIAKGSFVC IYAGKILTDD
FADKEGLEMG DEYFANLDHI ESVENFKEGY ESDAPCSSDS SGVDLKDQED GNSGTEDPEE
SNDDSSDDNF CKDEDFSTSS VWRSYATRRQ TRGQKENGLS ETTSKDSHPP DLGPPHIPVP
PSIPVGGCNP PSSEETPKNK VASWLSCNSV SEGGFADSDS HSSFKTNEGG EGRAGGSRME
AEKASTSGLG IKDEGDIKQA KKEDTDDRNK MSVVTESSRN YGYNPSPVKP EGLRRPPSKT
SMHQSRRLMA SAQSNPDDVL TLSSSTESEG ESGTSRKPTA GQTSATAVDS DDIQTISSGS
EGDDFEDKKN MTGPMKRQVA VKSTRGFALK STHGIAIKST NMASVDKGES APVRKNTRQF
YDGEESCYII DAKLEGNLGR YLNHSCSPNL FVQNVFVDTH DLRFPWVAFF ASKRIRAGTE
LTWDYNYEVG SVEGKELLCC CGAIECRGRL L
//
MIM
604396
*RECORD*
*FIELD* NO
604396
*FIELD* TI
*604396 SET DOMAIN PROTEIN, BIFURCATED, 1; SETDB1
;;ERG-ASSOCIATED PROTEIN WITH SET DOMAIN; ESET;;
read moreKIAA0067
*FIELD* TX
DESCRIPTION
The SET domain is a highly conserved, approximately 150-amino acid motif
implicated in the modulation of chromatin structure. It was originally
identified as part of a larger conserved region present in the
Drosophila Trithorax protein and was subsequently identified in the
Drosophila Su(var)3-9 and 'Enhancer of zeste' proteins, from which the
acronym SET is derived. Studies have suggested that the SET domain may
be a signature of proteins that modulate transcriptionally active or
repressed chromatin states through chromatin remodeling activities.
CLONING
By sequencing cDNAs randomly selected from a cDNA library derived from a
human immature myeloid cell line, Nomura et al. (1994) isolated a cDNA
encoding SETDB1, which they called KIAA0067. The deduced SETDB1 protein
has 1,291 amino acids. Northern blot analysis detected SETDB1 expression
in all 16 human tissues examined.
In the course of searching sequence databases for proteins containing
SET domains, Harte et al. (1999) identified the SETDB1 sequence. They
determined that SETDB1 has a C-terminal SET domain that is
well-conserved except that it contains a 347-amino acid insertion
between its most highly conserved regions. The authors found that the C.
elegans YNCA gene product is highly similar to SETDB1 and also contains
a bifurcated SET domain.
To identify interacting partners of ERG (165080), a transcription factor
that is implicated in the control of cell growth and differentiation,
Yang et al. (2002) screened a yeast 2-hybrid cDNA library constructed
from mouse hematopoietic cells using the N-terminal region of ERG as
bait. They isolated a full-length mouse Setdb1 cDNA, which they called
ESET, encoding a 1,307-amino acid protein migrating as a 180-kD band.
The mouse Setdb1 protein is 92% identical to human SETDB1.
GENE FUNCTION
Using 3 types of experiments, Yang et al. (2002) demonstrated
interaction between ESET and ERG. Since ESET possesses evolutionarily
conserved SET, preSET, and postSET domains implicated in histone
methylation, Yang et al. (2002) tested the ability of ESET to methylate
core histones. The results of these studies demonstrated that ESET is a
histone H3 (see 602810)-specific methyltransferase, and that mutations
within ESET abolished its methyltransferase activity. Yang et al. (2002)
suggested that transcription factor ERG may participate in
transcriptional regulation through ESET-mediated histone methylation.
Wang et al. (2003) identified AM (ATF7IP; 613644) as a HeLa cell protein
that copurified with SETDB1. They showed that recombinant mouse Am
increased the methyltransferase activity of recombinant mouse Setdb1
against H3 lys9 (H3K9). The methyltransferase activity of the
recombinant Am-Setdb1 complex was comparable to that of the endogenous
AM-SETDB1 complex purified from HeLa cells. Am increased the turnover
rate of the reaction by increasing Vmax and decreasing Km. In the
absence of Am, the predominant Setdb1 product was dimethylated H3K9, and
in the presence of Am, the predominant Setdb1 product was trimethylated
H3K9. These results were confirmed by small interfering RNA-mediated
knockdown of AM in HEK293 cells and HeLa cells. Use of a reconstituted
chromatin transcription system revealed that Am also enhanced the
transcriptional repression activity of Setdb1.
Matsui et al. (2010) showed that the H3K9 methyltransferase ESET and the
Kruppel-associated box-associated protein-1 (KAP1; 601742) are required
for H3K9 trimethylation (H3K9me3) and silencing of endogenous and
introduced retroviruses specifically in mouse embryonic stem (ES) cells.
Furthermore, whereas ESET enzymatic activity is crucial for binding
heterochromatin protein-1 (HP1; 604478) and efficient proviral
silencing, the H4K20 methyltransferases Suv420h1 (610881) and Suv420h2
(613198) are dispensable for silencing. Notably, in mouse ES cells null
for 3 DNA methyltransferases (Dnmt1, 126375; Dnmt3a, 602769; Dnmt3b,
602900), ESET and KAP1 binding and ESET-mediated H3K9me3 were maintained
and ERVs (endogenous retroviruses) were minimally derepressed. Matsui et
al. (2010) proposed that a DNA methylation-independent pathway involving
KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing
during the period early in embryogenesis when DNA methylation is
dynamically reprogrammed.
Ceol et al. (2011) used a zebrafish melanoma model to test genes in a
recurrently amplified region of chromosome 1 for the ability to
cooperate with BRAF(V600E) (164757.0001) and accelerate melanoma.
SETDB1, an enzyme that methylates histone H3 (see 601128) on lysine-9
(H3K9), was found to accelerate melanoma formation significantly in
zebrafish. Chromatin immunoprecipitation coupled with massively parallel
DNA sequencing and gene expression analyses uncovered genes, including
HOX genes (e.g., 142950), that are transcriptionally dysregulated in
response to increased levels of SETDB1. Ceol et al. (2011) concluded
that their studies established SETDB1 as an oncogene in melanoma and
underscored the role of chromatin factors in regulating tumorigenesis.
MAPPING
Nomura et al. (1994) mapped the SETDB1 gene to chromosome 1 using a
somatic cell hybrid mapping panel. By FISH and radiation hybrid mapping,
Harte et al. (1999) localized the gene to 1q21.
*FIELD* RF
1. Ceol, C. J.; Houvras, Y.; Jane-Valbuena, J.; Bilodeau, S.; Orlando,
D. A.; Battisti, V.; Fritsch, L.; Lin, W. M.; Hollmann, T. J.; Ferre,
F.; Bourque, C.; Burke, C. J.; and 10 others: The histone methyltransferase
SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature 471:
513-517, 2011.
2. Harte, P. J.; Wu, W.; Carrasquillo, M. M.; Matera, A. G.: Assignment
of a novel bifurcated SET domain gene, SETDB1, to human chromosome
band 1q21 by in situ hybridization and radiation hybrids. Cytogenet.
Cell Genet. 84: 83-86, 1999.
3. Matsui, T.; Leung, D.; Miyashita, H.; Maksakova, I. A.; Miyachi,
H.; Kimura, H.; Tachibana, M.; Lorincz, M. C.; Shinkai, Y.: Proviral
silencing in embryonic stem cells requires the histone methyltransferase
ESET. Nature 464: 927-931, 2010.
4. Nomura, N.; Nagase, T.; Miyajima, N.; Sazuka, T.; Tanaka, A.; Sato,
S.; Seki, N.; Kawarabayasi, Y.; Ishikawa, K.; Tabata, S.: Prediction
of the coding sequences of unidentified human genes. II. The coding
sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis
of cDNA clones from human cell line KG-1. DNA Res. 1: 223-229, 1994.
5. Wang, H.; An, W.; Cao, R.; Xia, L.; Erdjument-Bromage, H.; Chatton,
B.; Tempst, P.; Roeder, R. G.; Zhang, Y.: mAM facilitates conversion
by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional
repression. Molec. Cell 12: 475-487, 2003.
6. Yang, L.; Xia, L.; Wu, D. Y.; Wang, H.; Chansky, H. A.; Schubach,
W. H.; Hickstein, D. D.; Zhang, Y.: Molecular cloning of ESET, a
novel histone H3-specific methyltransferase that interacts with ERG
transcription factor. Oncogene 21: 148-152, 2002.
*FIELD* CN
Ada Hamosh - updated: 5/9/2011
Patricia A. Hartz - updated: 11/17/2010
Ada Hamosh - updated: 5/26/2010
*FIELD* CD
Patti M. Sherman: 12/30/1999
*FIELD* ED
mgross: 02/05/2013
alopez: 5/10/2011
terry: 5/9/2011
mgross: 11/17/2010
alopez: 5/27/2010
terry: 5/26/2010
carol: 2/19/2002
joanna: 2/5/2002
mgross: 1/4/2000
psherman: 1/3/2000
*RECORD*
*FIELD* NO
604396
*FIELD* TI
*604396 SET DOMAIN PROTEIN, BIFURCATED, 1; SETDB1
;;ERG-ASSOCIATED PROTEIN WITH SET DOMAIN; ESET;;
read moreKIAA0067
*FIELD* TX
DESCRIPTION
The SET domain is a highly conserved, approximately 150-amino acid motif
implicated in the modulation of chromatin structure. It was originally
identified as part of a larger conserved region present in the
Drosophila Trithorax protein and was subsequently identified in the
Drosophila Su(var)3-9 and 'Enhancer of zeste' proteins, from which the
acronym SET is derived. Studies have suggested that the SET domain may
be a signature of proteins that modulate transcriptionally active or
repressed chromatin states through chromatin remodeling activities.
CLONING
By sequencing cDNAs randomly selected from a cDNA library derived from a
human immature myeloid cell line, Nomura et al. (1994) isolated a cDNA
encoding SETDB1, which they called KIAA0067. The deduced SETDB1 protein
has 1,291 amino acids. Northern blot analysis detected SETDB1 expression
in all 16 human tissues examined.
In the course of searching sequence databases for proteins containing
SET domains, Harte et al. (1999) identified the SETDB1 sequence. They
determined that SETDB1 has a C-terminal SET domain that is
well-conserved except that it contains a 347-amino acid insertion
between its most highly conserved regions. The authors found that the C.
elegans YNCA gene product is highly similar to SETDB1 and also contains
a bifurcated SET domain.
To identify interacting partners of ERG (165080), a transcription factor
that is implicated in the control of cell growth and differentiation,
Yang et al. (2002) screened a yeast 2-hybrid cDNA library constructed
from mouse hematopoietic cells using the N-terminal region of ERG as
bait. They isolated a full-length mouse Setdb1 cDNA, which they called
ESET, encoding a 1,307-amino acid protein migrating as a 180-kD band.
The mouse Setdb1 protein is 92% identical to human SETDB1.
GENE FUNCTION
Using 3 types of experiments, Yang et al. (2002) demonstrated
interaction between ESET and ERG. Since ESET possesses evolutionarily
conserved SET, preSET, and postSET domains implicated in histone
methylation, Yang et al. (2002) tested the ability of ESET to methylate
core histones. The results of these studies demonstrated that ESET is a
histone H3 (see 602810)-specific methyltransferase, and that mutations
within ESET abolished its methyltransferase activity. Yang et al. (2002)
suggested that transcription factor ERG may participate in
transcriptional regulation through ESET-mediated histone methylation.
Wang et al. (2003) identified AM (ATF7IP; 613644) as a HeLa cell protein
that copurified with SETDB1. They showed that recombinant mouse Am
increased the methyltransferase activity of recombinant mouse Setdb1
against H3 lys9 (H3K9). The methyltransferase activity of the
recombinant Am-Setdb1 complex was comparable to that of the endogenous
AM-SETDB1 complex purified from HeLa cells. Am increased the turnover
rate of the reaction by increasing Vmax and decreasing Km. In the
absence of Am, the predominant Setdb1 product was dimethylated H3K9, and
in the presence of Am, the predominant Setdb1 product was trimethylated
H3K9. These results were confirmed by small interfering RNA-mediated
knockdown of AM in HEK293 cells and HeLa cells. Use of a reconstituted
chromatin transcription system revealed that Am also enhanced the
transcriptional repression activity of Setdb1.
Matsui et al. (2010) showed that the H3K9 methyltransferase ESET and the
Kruppel-associated box-associated protein-1 (KAP1; 601742) are required
for H3K9 trimethylation (H3K9me3) and silencing of endogenous and
introduced retroviruses specifically in mouse embryonic stem (ES) cells.
Furthermore, whereas ESET enzymatic activity is crucial for binding
heterochromatin protein-1 (HP1; 604478) and efficient proviral
silencing, the H4K20 methyltransferases Suv420h1 (610881) and Suv420h2
(613198) are dispensable for silencing. Notably, in mouse ES cells null
for 3 DNA methyltransferases (Dnmt1, 126375; Dnmt3a, 602769; Dnmt3b,
602900), ESET and KAP1 binding and ESET-mediated H3K9me3 were maintained
and ERVs (endogenous retroviruses) were minimally derepressed. Matsui et
al. (2010) proposed that a DNA methylation-independent pathway involving
KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing
during the period early in embryogenesis when DNA methylation is
dynamically reprogrammed.
Ceol et al. (2011) used a zebrafish melanoma model to test genes in a
recurrently amplified region of chromosome 1 for the ability to
cooperate with BRAF(V600E) (164757.0001) and accelerate melanoma.
SETDB1, an enzyme that methylates histone H3 (see 601128) on lysine-9
(H3K9), was found to accelerate melanoma formation significantly in
zebrafish. Chromatin immunoprecipitation coupled with massively parallel
DNA sequencing and gene expression analyses uncovered genes, including
HOX genes (e.g., 142950), that are transcriptionally dysregulated in
response to increased levels of SETDB1. Ceol et al. (2011) concluded
that their studies established SETDB1 as an oncogene in melanoma and
underscored the role of chromatin factors in regulating tumorigenesis.
MAPPING
Nomura et al. (1994) mapped the SETDB1 gene to chromosome 1 using a
somatic cell hybrid mapping panel. By FISH and radiation hybrid mapping,
Harte et al. (1999) localized the gene to 1q21.
*FIELD* RF
1. Ceol, C. J.; Houvras, Y.; Jane-Valbuena, J.; Bilodeau, S.; Orlando,
D. A.; Battisti, V.; Fritsch, L.; Lin, W. M.; Hollmann, T. J.; Ferre,
F.; Bourque, C.; Burke, C. J.; and 10 others: The histone methyltransferase
SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature 471:
513-517, 2011.
2. Harte, P. J.; Wu, W.; Carrasquillo, M. M.; Matera, A. G.: Assignment
of a novel bifurcated SET domain gene, SETDB1, to human chromosome
band 1q21 by in situ hybridization and radiation hybrids. Cytogenet.
Cell Genet. 84: 83-86, 1999.
3. Matsui, T.; Leung, D.; Miyashita, H.; Maksakova, I. A.; Miyachi,
H.; Kimura, H.; Tachibana, M.; Lorincz, M. C.; Shinkai, Y.: Proviral
silencing in embryonic stem cells requires the histone methyltransferase
ESET. Nature 464: 927-931, 2010.
4. Nomura, N.; Nagase, T.; Miyajima, N.; Sazuka, T.; Tanaka, A.; Sato,
S.; Seki, N.; Kawarabayasi, Y.; Ishikawa, K.; Tabata, S.: Prediction
of the coding sequences of unidentified human genes. II. The coding
sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis
of cDNA clones from human cell line KG-1. DNA Res. 1: 223-229, 1994.
5. Wang, H.; An, W.; Cao, R.; Xia, L.; Erdjument-Bromage, H.; Chatton,
B.; Tempst, P.; Roeder, R. G.; Zhang, Y.: mAM facilitates conversion
by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional
repression. Molec. Cell 12: 475-487, 2003.
6. Yang, L.; Xia, L.; Wu, D. Y.; Wang, H.; Chansky, H. A.; Schubach,
W. H.; Hickstein, D. D.; Zhang, Y.: Molecular cloning of ESET, a
novel histone H3-specific methyltransferase that interacts with ERG
transcription factor. Oncogene 21: 148-152, 2002.
*FIELD* CN
Ada Hamosh - updated: 5/9/2011
Patricia A. Hartz - updated: 11/17/2010
Ada Hamosh - updated: 5/26/2010
*FIELD* CD
Patti M. Sherman: 12/30/1999
*FIELD* ED
mgross: 02/05/2013
alopez: 5/10/2011
terry: 5/9/2011
mgross: 11/17/2010
alopez: 5/27/2010
terry: 5/26/2010
carol: 2/19/2002
joanna: 2/5/2002
mgross: 1/4/2000
psherman: 1/3/2000