Enhancer Activity Requires CBP/P300 Bromodomain Dependent Histone H3K27 Acetylation

Acetylation of Histone H3 at lysine 27 is a well-defined marker of enhancer activity, however, the functional impact of this modification at enhancers is poorly understood. We have used a chemical genetics approach to acutely block the function of the CBP/P300 bromodomain in models of hematological and endocrine cancers, and describe a consequent loss of H3K27Ac specifically from enhancers, despite the continued presence of CBP/P300 at chromatin. Using this approach to dissect the role of H3K27Ac at enhancers, we identify a critical role for this modification in the production of enhancer RNAs, and transcription of enhancer-regulated gene networks. This work offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat a variety of cancers.