Covalent modifications of histone tails play important roles in gene 
transcription and silencing. We recently identified an ERG ( ets -related 
gene)-associated protein with a SET (suppressor of variegation, enhancer of zest 
and trithorax) domain (ESET) that was found to have the activity of a histone 
H3-specific methyltransferase. In the present study, we investigated the 
interaction of ESET with other chromatin remodelling factors. We show that ESET 
histone methyltransferase associates with histone deacetylase 1 (HDAC1) and 
HDAC2, and that ESET also interacts with the transcription co-repressors mSin3A 
and mSin3B. Deletion analysis of ESET reveals that an N-terminal region 
containing a tudor domain is responsible for interaction with mSin3A/B and 
association with HDAC1/2, and that truncation of ESET enhances its binding to 
mSin3. When bound to a promoter, ESET represses the transcription of a 
downstream luciferase reporter gene. This repression by ESET is independent of 
its histone methyltransferase activity, but correlates with its binding to the 
mSin3 co-repressors. In addition, the repression can be partially reversed by 
treatment with the HDAC inhibitor trichostatin A. Taken together, these data 
suggest that ESET histone methyltransferase can form a large, multi-protein 
complex(es) with mSin3A/B co-repressors and HDAC1/2 that participates in 
multiple pathways of transcriptional repression.