Double PHD Fingers Protein DPF2 Recognizes Acetylated Histones and Suppresses the Function of Estrogen-related Receptor a through Histone Deacetylase 1

Estrogen-related receptor a (ERRa) is a member of the nuclear receptor superfamily and regulates many physiological functions, including mitochondrial biogenesis and lipid metabolism. ERRa enhances the transactivation function without endogenous ligand by associating with coactivators such as peroxisome proliferator-activated receptor g coactivator 1 a and b (PGC-1a and -b) and members of the steroid receptor coactivator family. However, the molecular mechanism by which the transactivation function of ERRa is converted from a repressive state to an active state is poorly understood. Here we used biochemical purification techniques to identify ERRa-associated proteins in HeLa cells stably expressing ERRa. Interestingly, we found that double PHD fingers protein DPF2/BAF45d suppressed PGC-1a-dependent transactivation of ERRa by recognizing acetylated histone H3 and associating with HDAC1. DPF2 directly bound to ERRa and suppressed the transactivation function of nuclear receptors such as androgen receptor. DPF2 was recruited to ERR target gene promoters in myoblast cells, and knockdown of DPF2 derepressed the level of mRNA expressed by target genes of ERRa. These results show that DPF2 acts as a nuclear receptor-selective co-repressor for ERRa by associating with both acetylated histone H3 and HDAC1.