The Erg­associated protein with SET domain (ESET), also known as SET domain, bifurcated 1 (SETDB1) protein, is a member of a family of histone lysine methyltransferases, each of which contains a conserved catalytic SET domain originally identified in Drosophila, Enhancer of zeste, and Trithorax proteins. ESET also contains tudor and methyl­CpG­binding domains, which may coordinate binding to methylated histones and methylated DNA, respectively. ESET methylates histone H3 Lys9, creating a transcriptionally repressive mark that facilitates gene silencing. However, unlike SUV39H histone H3 Lys9 methyltransferases, which function mainly in heterochromatin regions such as pericentric heterochromatin, ESET functions mainly in euchromatic regions to repress gene promoters. ESET interacts with a variety of proteins, including transcription factors (ERG), histone deacetylases (HDAC1/2), DNA methyltransferases (DNMT3A/B) and transcriptional co­repressors (mSin3A/B, MBD1, KAP­1, the ATFa­associated modulator mAM). mAM forms a complex with ESET, stimulating its methyltransferase activity, specifically the conversion of di­methyl to tri­methyl histone H3 Lys9. MBD1 recruits ESET to the CAF­1 complex to facilitate methylation of histone H3 Lys9 during replication­coupled chromatin assembly in S phase. DNMT3A recruits ESET to silenced promoters in cancer cells. ESET may play a role in the pathogenesis of Huntington's disease, since levels of ESET protein and tri­methyl histone H3 Lys9 are both increased in diseased brains.