The function of SETDB1 (SET domain bifurcated histone lysine methyltransferase 1, Ensembl gene identifier ENSG00000143379) is as follows. Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3 (H3K9me3) (PubMed:11959841, PubMed:12869583, PubMed:14536086, PubMed:27237050, PubMed:39096901). H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones (PubMed:11959841, PubMed:12869583, PubMed:14536086, PubMed:27237050, PubMed:39096901). Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes (PubMed:12869583, PubMed:14536086, PubMed:27237050, PubMed:39096901). H3 'Lys-9' trimethylation is coordinated with DNA methylation (PubMed:12869583, PubMed:14536086, PubMed:27237050, PubMed:39096901). Forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation (PubMed:14536086). Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1 (PubMed:14536086). SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins (PubMed:24623306). Required for HUSH-mediated heterochromatin formation and gene silencing (PubMed:27732843). 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 (PubMed:37938770). 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). Also catalyzes mono- and dimethylation of 'Lys-9' of free histone H3 (H3K9me1 and H3K9me2) during translation in the cytoplasm, which is then transported to the nucleus and incorporated into nucleosomes (PubMed:26405197). {ECO:0000269|PubMed:11959841, ECO:0000269|PubMed:12869583, ECO:0000269|PubMed:14536086, ECO:0000269|PubMed:24623306, ECO:0000269|PubMed:26405197, ECO:0000269|PubMed:27029610, ECO:0000269|PubMed:27237050, ECO:0000269|PubMed:27732843, ECO:0000269|PubMed:37938770, ECO:0000269|PubMed:39096901}. [Isoform 2]: Lacks all domains required for histone methyltransferase activity. .