An acetylation switch modulates the transcriptional activity of estrogen-related receptor alpha.
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 (ERRalpha, NR3B1) is phosphorylated on multiple sites, and sumoylated in the amino-terminal region in a phosphorylation-dependent manner. Here we demonstrate that ERRalpha 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 ERRalpha on four highly-conserved lysines. In addition, coexpression of PCAF reduced the transcriptional activity of ERRalpha and, reciprocally, a deacetylase screen identified histone deacetylase 8 (HDAC8) and sirtuin 1 homolog (Sirt1) as independent enhancers of ERRalpha transcriptional function. HDAC8 and Sirt1 were also demonstrated to interact directly with ERRalpha in vivo and to deacetylate and increase the DNA binding affinity of ERRalpha in vitro. The removal of PCAF increases the DNA binding of ERRalpha in vivo, whereas the removal of Sirt1 and HDAC8 decreases it as assessed by chromatin immunoprecipitation assay. Altogether, our results show that ERRalpha is an acetylated protein and imply the existence of a dynamic acetylation/deacetylation switch involved in the control of ERRalpha transcriptional activity.
Wilson
Brian J
BJ
Rosalind and Morris Goodman Cancer Research Centre, Montréal, Québec, Canada H3A1A3.
Tremblay
Annie M
AM
Deblois
Geneviève
G
Sylvain-Drolet
Guillaume
G
Giguère
Vincent
V
D000107:Acetylation; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor; D000099224:p300-CBP-Associated Factor
D006655:Histone Deacetylases; D011960:Receptors, Estrogen; D056564:Sirtuin 1; D050880:p300-CBP Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; D000099224:p300-CBP-Associated Factor; C470545:Sirt1 protein, mouse; C000603105:HDAC8 protein, mouse