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

Regulation of nuclear receptor gene expression involves dynamic and coordinated interactions with histone acetyl transferase (HAT) and deacetylase complexes. The estrogen receptor (ER alpha) contains two transactivation domains regulating ligand-independent and -dependent gene transcription (AF-1 and 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 ER alpha is acetylated in vivo, p300, but not P/CAF, selectively and directly acetylated the ER alpha at lysine residues within the ER alpha hinge/ligand binding domain. Substitution of these residues with charged or polar residues dramatically enhanced ER alpha hormone sensitivity without affecting induction by MAPK signaling, suggesting that direct ER alpha acetylation normally suppresses ligand sensitivity. These ER alpha lysine residues also regulated transcriptional activation by histone deacetylase inhibitors and p300, The conservation of the ER alpha acetylation motif in a phylogenetic subset of nuclear receptors suggests that direct acetylation of nuclear receptors may contribute to additional signaling pathways involved in metabolism and development.