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)

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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-[[[A137031|histone]]] = S-adenosyl-L-homocysteine + N(6)-methyl-L-lysine-[[[A137031|histone]]]

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

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