Summary: 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. Here, we use a chemical genetics approach to acutely block the function of the cAMP response element binding protein (CREB) binding protein (CBP)/P300 bromodomain in models of hematological malignancies 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. : Raisner et al. demonstrate that CBP/P300 bromodomain inhibition reduces levels of the H3K27Ac histone modification specifically at enhancers. Known to be correlated with enhancer activity, the authors find this modification to be essential for enhancer activation, associated gene expression, and proliferation of hematological malignancies. Keywords: enhancer, P300, CBP, bromodomain, histone acetylation, H3K27Ac
