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

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2010-07, Vol.24 (7), p.1349-1358
• Main Authors: Wilson, Brian J, Tremblay, Annie M, Deblois, Geneviève, Sylvain-Drolet, Guillaume, Giguère, Vincent
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Cell Line; Chlorocebus aethiops; Chromatin Immunoprecipitation; COS Cells; Electrophoretic Mobility Shift Assay; ERRalpha Estrogen-Related Receptor; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Immunoblotting; Immunoprecipitation; Mass Spectrometry; Mice; Original Research; p300-CBP Transcription Factors - genetics; p300-CBP Transcription Factors - metabolism; Protein Binding; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Transcription, Genetic - genetics
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2009-0441

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 α (ERRα, NR3B1) is phosphorylated on multiple sites, and sumoylated in the amino-terminal region in a phosphorylation-dependent manner. Here we demonstrate that ERRα 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 ERRα on four highly-conserved lysines. In addition, coexpression of PCAF reduced the transcriptional activity of ERRα and, reciprocally, a deacetylase screen identified histone deacetylase 8 (HDAC8) and sirtuin 1 homolog (Sirt1) as independent enhancers of ERRα transcriptional function. HDAC8 and Sirt1 were also demonstrated to interact directly with ERRα in vivo and to deacetylate and increase the DNA binding affinity of ERRα in vitro. The removal of PCAF increases the DNA binding of ERRα in vivo, whereas the removal of Sirt1 and HDAC8 decreases it as assessed by chromatin immunoprecipitation assay. Altogether, our results show that ERRα is an acetylated protein and imply the existence of a dynamic acetylation/deacetylation switch involved in the control of ERRα transcriptional activity. This study reveals the existence of a dynamic acetylation/deacetylation switch involved in the control of ERRα transcriptional activity.