An Acetylation Switch Modulates the Transcriptional Activity of Estrogen-Related Receptor α

Posttranslational modifications are instrumental to achieve gene-and tissue-specific regulatory outcomes by transcription factors. Nuclear receptors are dynamically modulated by several types of posttranslational modifications including phosphorylation, methylation, acetylation, ubiquitination, and sumoylation. The estrogen-related receptor alpha (ERR alpha, NR3B1) is phosphorylated on multiple sites, and sumoylated in the amino-terminal region in a phosphorylation-dependent manner. Here we demonstrate that ERR alpha interacts with and is acetylated by p300 coactivator associated factor (PCAF) in vitro and in mouse liver. Purified PCAF acetylated the DNA-binding domain of ERR alpha on four highly-conserved lysines. In addition, coexpression of PCAF reduced the transcriptional activity of ERR alpha and, reciprocally, a deacetylase screen identified histone deacetylase 8 (HDAC8) and sirtuin 1 homolog (Sirt1) as independent enhancers of ERR alpha transcriptional function. HDAC8 and Sirt1 were also demonstrated to interact directly with ERR alpha in vivo and to deacetylate and increase the DNA binding affinity of ERR alpha in vitro. The removal of PCAF increases the DNA binding of ERR alpha in vivo, whereas the removal of Sirt1 and HDAC8 decreases it as assessed by chromatin immunoprecipitation assay. Altogether, our results show that ERR alpha is an acetylated protein and imply the existence of a dynamic acetylation/deacetylation switch involved in the control of ERR alpha transcriptional activity. (Molecular Endocrinology 24: 1349-1358, 2010)