Transcription factor dimerization activates the p300 acetyltransferase

The transcriptional coactivator p300 is a histone lysine acetyltransferase that is typically recruited to transcriptional enhancers and regulates gene expression by acetylating chromatin. Here we show that p300 activation directly depends on the activation and oligomerisation status of transcription factor (TF) ligands. Using two model TFs, IRF3 and STAT1, we demonstrate that TF dimerization enables trans-autoacetylation of p300 in a highly conserved and intrinsically disordered autoinhibitory lysine-rich loop (AIL), resulting in HAT activation. We describe a p300 crystal structure in which the AIL invades the active site of a neighbouring HAT domain thus revealing a snap-shot of a trans-autoacetylation reaction intermediate. Substrate access to the active site involves rearrangement of an autoinhibitory RING domain. Our data explain how cellular signalling, TF activation and dimerization controls p300 activation thus explaining why gene transcription is associated with chromatin acetylation.