SETDB1

This gene encodes a histone methyltransferase which regulates histone methylation, gene silencing, and transcriptional repression. This gene has been identified as a target for treatment in Huntington Disease, given that gene silencing and transcription dysfunction likely play a role in the disease pathogenesis. Alternatively spliced transcript variants of this gene have been described.[provided by RefSeq, Jun 2011]

SET Domain Bifurcated 1

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).
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,). 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).

Biological Process heterochromatin organizationManual Assertion Based On ExperimentIBA:GO_Central
Biological Process histone H3-K9 methylationManual Assertion Based On ExperimentIBA:GO_Central
Biological Process negative regulation of gene expressionManual Assertion Based On ExperimentIBA:GO_Central
Biological Process negative regulation of single stranded viral RNA replication via double stranded DNA intermediateISS:UniProtKB
Biological Process positive regulation of DNA methylation-dependent heterochromatin assemblyManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process Ras protein signal transductionManual Assertion Based On ExperimentIMP:UniProtKB

Nucleus
Cytoplasm
Chromosome
Associated with non-pericentromeric regions of chromatin. Excluded from nucleoli and islands of condensed chromatin.

Degraded by the proteasome, shielded by interaction with ATF7IP.