Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity

Regulation of nuclear receptor gene expression involves dynamic and coordin ated interactions with histone acetyl transferase (HAT) and deacetylase com plexes. The estrogen receptor (ER alpha) contains two transactivation domai ns regulating ligand-independent and -dependent gene transcription (AF-1 an d AF-2 (activation functions 1 and 2)). ER alpha -regulated gene expression involves interactions with cointegrators (e.g. p300/ CBP, P/CAF) that have the capacity to modify core histone acetyl groups. Here we show that the E R alpha is acetylated in vivo, p300, but not P/CAF, selectively and directl y acetylated the ER alpha at lysine residues within the ER alpha hinge/liga nd binding domain. Substitution of these residues with charged or polar res idues dramatically enhanced ER alpha hormone sensitivity without affecting induction by MAPK signaling, suggesting that direct ER alpha acetylation no rmally suppresses ligand sensitivity. These ER alpha lysine residues also r egulated transcriptional activation by histone deacetylase inhibitors and p 300, The conservation of the ER alpha acetylation motif in a phylogenetic s ubset of nuclear receptors suggests that direct acetylation of nuclear rece ptors may contribute to additional signaling pathways involved in metabolis m and development.