Receptor-interacting protein 140 directly recruits histone deacetylases for gene silencing

Receptor-interacting protein 140 (RIP140) encodes a histone deacetylase (HD AC) inhibitor-sensitive repressive activity. Direct interaction of RIP140 w ith HDAC1 and HDAC3 occurs in vitro and in vivo as demonstrated in co-immun oprecipitation and glutathione S-transferase pull-down experiments. The HDA C-interacting domain of RIP140 is mapped to its N-terminal domain, between amino acids 78 and 303 based upon glutathione S-transferase pull-down exper iments. In chromatin immunoprecipitation assays, it is demonstrated that hi stone deacetylation occurs at the chromatin region of the Ga14 binding site s as a result of Ga14 DNA binding domain-tethered RIP expression. The immun ocomplexes of RIP140 from cells transfected with RIP140 and HDAC are able t o deacetylate histone proteins in vitro. This study presents the first evid ence for RIP140 as a negative coregulator for nuclear receptor actions by d irectly recruiting histone deacetylases and categorizes RIP140 as a novel n egative coregulator that is able to directly interact with HDACs.