An Acetylation Switch Modulates the Transcriptional Activity of Estrogen-Related Receptor [alpha].
Wilson, Brian J. *; Tremblay, Annie M. *; Deblois, Genevieve; Sylvain-Drolet, Guillaume; Giguere, Vincent
[Article]
Molecular Endocrinology.
24(7):1349-1358, July 2010.
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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.
Copyright (C) 2010 by The Endocrine Society