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

Ryan Raisner; Samir Kharbanda; Lingyan Jin; Edwin Jeng; Emily Chan; Mark Merchant; Peter M Haverty; Russell Bainer; Tommy Cheung; David Arnott; E Megan Flynn; F Anthony Romero; Steven Magnuson; Karen E Gascoigne

doi:10.1016/j.celrep.2018.07.041

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.

Authors

Ryan Raisner¹, Samir Kharbanda², Lingyan Jin¹, Edwin Jeng³, Emily Chan⁴, Mark Merchant⁴, Peter M Haverty⁵, Russell Bainer⁵, Tommy Cheung⁶, David Arnott⁶, E Megan Flynn⁷, F Anthony Romero⁸, Steven Magnuson⁹, Karen E Gascoigne¹⁰

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: gascoigne.karen@gene.com.

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.

MeSH terms

Acetylation
Binding Sites
Cell Line, Tumor
Chromatin / chemistry
Chromatin / metabolism
Enhancer Elements, Genetic*
Hematologic Neoplasms / genetics
Hematologic Neoplasms / metabolism
Histones / genetics
Histones / metabolism*
Humans
Lysine / metabolism
Protein Binding
Protein Domains
Protein Processing, Post-Translational*
RNA, Neoplasm / genetics*
RNA, Neoplasm / metabolism
Transcription, Genetic
p300-CBP Transcription Factors / genetics*
p300-CBP Transcription Factors / metabolism

Substances

Chromatin
Histones
RNA, Neoplasm
p300-CBP Transcription Factors
Lysine