histone-lysine N-methyltransferase SETDB1; ERG-associated protein with SET domain; ESET; histone H3-K9 methyltransferase 4; H3-K9-HMTase 4; lysine N-methyltransferase 1E; SET domain bifurcated 1 (SETDB1, KIAA0067, KMT1E)

Function: - histone methyltransferase - specifically trimethylates Lys-9 of histone H3 - H3 Lys-9 trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 &/or CBX5) proteins to methylated histones - mainly functions in euchromatin regions, thus playing a role in the silencing of euchromatic genes - H3 Lys-9 trimethylation is coordinated with DNA methylation - probably forms a complex with MBD1 & ATF7IP that represses transcription & couples DNA methylation & histone Lys-9 trimethylation - activity is dependent on MBD1 & is maintained through DNA replication by being recruited by CAF-1 - SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB Zn⁺²-finger proteins - interacts with MBD1; interaction is abolished when MBD1 is sumoylated - interacts with ATF7IP & ATF7IP2; the interaction with ATF7IP is required to stimulate histone methyltransferase activity & facilitate the conversion of dimethylated to trimethylated H3 Lys-9 - during DNA replication, it is recruited by SETDB1 to form a S phase-specific complex that facilitates methylation of H3 Lys-9 during replication-coupled chromatin assembly - the S phase-specific complex is at least composed of the CAF-1 subunit CHAF1A, MBD1 & SETDB1 - interacts with ERG, TRIM28/TIF1B, CBX1, CBX5, CHD7, DNMT3A, HDAC1, HDAC2, NLK, PPARG, SIN3A, SIN3B, DNMT3B & SUMO₂ - interacts with MBD1; interaction is abolished when MBD1 is sumoylated S-adenosyl-L-methionine + L-lysine-[histone] = S-adenosyl-L-homocysteine + N(6)-methyl-L-lysine-[histone] Structure: - the pre-SET, SET & post-SET domains are all required for methyltransferase activity. the 347-amino-acid insertion in the SET domain has no effect on the catalytic activity - isoform 2 lacks all domains required for histone methyltransferase activity - belongs to the histone-lysine methyltransferase family, Suvar3-9 subfamily - contains 1 MBD (methyl-CpG-binding) domain - contains 1 post-SET domain - contains 1 pre-SET domain - contains 1 SET domain - contains 2 Tudor domains Compartment: - nucleus, chromosome - associated with non-pericentromeric regions of chromatin - excluded from nucleoli & islands of condensed chromatin Alternative splicing: named isoforms=3 Expression: - widely expressed - high expression in testis Pathology: - highly up-regulated in Huntington disease (HD) patients, suggesting that participates in the altered chromatin modulation & transcription dysfunction observed in Huntington disease - down-regulation of SETDB1 has favorable effects on HD patients

General

histone N-methyltransferase phosphoprotein

Properties

SIZE: entity length = 1291 aa MW = 143 kD COMPARTMENT: cell nucleus MOTIF: coiled coil {18-64} Ser phosphorylation site {S175} Tudor domain SITE: 257-320 Tudor domain SITE: 347-403 MBD {594-665} pre-SET domain {727-800} SET domain {802-1270} MOTIF: Thr phosphorylation site {T838} Thr phosphorylation site {T976} Ser phosphorylation site {S1066} Ser phosphorylation site {S1179} Thr phosphorylation site {T1180} Ser phosphorylation site {S1190} post-SET domain {1275-1291}

Database Correlations

OMIM 604396 UniProt Q15047 PFAM correlations Entrez Gene 9869 Kegg hsa:9869 ENZYME 2.1.1.43

References

UniProt :accession Q15047