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