SETDB1, Histone-lysine N-methyltransferase SETDB1
Enzyme Classification 18.104.22.168
Also Known as
SETB1_HUMAN, SETDB1, ESET, KIAA0067, KMT1E
Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3. H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. H3 'Lys-9' trimethylation is coordinated with DNA methylation (PubMed:12869583, PubMed:17952062). Required for HUSH-mediated heterochromatin formation and gene silencing. Forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation (PubMed:27732843, PubMed:14536086). Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1 (PubMed:14536086, PubMed:15327775). SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells (PubMed:24623306). Required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). In ESCs, in collaboration with TRIM28, is also required for H3K9me3 and silencing of endogenous and introduced retroviruses in a DNA-methylation independent-pathway (By similarity). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing (PubMed:24623306). The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3'-exons of zinc-finger coding genes with atypical chromatin signatures to establish or maintain/protect H3K9me3 at these transcriptionally active regions (PubMed:27029610). Part of a complex containing at least CDYL, REST, WIZ, SETDB1, EHMT1 and EHMT2 (PubMed:19061646). 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 and is at least composed of the CAF-1 subunit CHAF1A, MBD1 and SETDB1 (PubMed:15327775). Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1 (PubMed:24623306). Interacts with TRIM28/TIF1B (PubMed:11959841). Interacts with ATF7IP and ATF7IP2; the interaction with ATF7IP protects SETDB1 from proteasomal degradation and is required to stimulate histone methyltransferase activity and facilitate the conversion of dimethylated to trimethylated H3 'Lys-9' (PubMed:14536086, PubMed:15691849). Interacts with MBD1; interaction is abolished when MBD1 is sumoylated (PubMed:15327775, PubMed:17066076). Interacts with CBX1 and CBX5 (PubMed:15899859). Interacts with DNMT3A and DNMT3B (PubMed:16682412). Interacts with SUMO2. Interacts with CHD7, NLK1 and PPARG (PubMed:17952062). Interacts with MPHOSPH8 (PubMed:20871592). Interacts with ERG (By similarity). Interacts with HDAC1, HDAC2, SIN3A and SIN3B (By similarity). Interacts with ATRX. Forms a complex with ATRX, TRIM28 and ZNF274 (PubMed:27029610). Interacts with RESF1.