Enhancer Activity Requires CBP/P300 Bromodomain-Dependent Histone H3K27 Acetylation

  • Cell Rep. 2018 Aug 14;24(7):1722-1729. doi: 10.1016/j.celrep.2018.07.041.
Ryan Raisner  1 ,  Samir Kharbanda  2 ,  Lingyan Jin  1 ,  Edwin Jeng  3 ,  Emily Chan  4 ,  Mark Merchant  4 ,  Peter M Haverty  5 ,  Russell Bainer  5 ,  Tommy Cheung  6 ,  David Arnott  6 ,  E Megan Flynn  7 ,  F Anthony Romero  8 ,  Steven Magnuson  9 ,  Karen E Gascoigne  10
Affiliations
  • 1. Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.
  • 2. Calico Labs, South San Francisco, CA 94080, USA.
  • 3. Program in Cancer Biology and Department of Genetics, Stanford University, Stanford, CA 94305, USA.
  • 4. Department of Translational Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.
  • 5. Department of Bioinformatics, Genentech, Inc., South San Francisco, CA 94080, USA.
  • 6. Department of Protein Science, Genentech, Inc., South San Francisco, CA 94080, USA.
  • 7. Department of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
  • 8. Unity Biotechnology, Brisbane, CA 94005, USA.
  • 9. Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
  • 10. Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address: [email protected].
PMID: 30110629 DOI: 10.1016/j.celrep.2018.07.041
Abstract

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.

Keywords
CBP; H3K27Ac; P300; bromodomain; enhancer; histone acetylation.