Bromodomain Protein BRD4 Is Required for Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription

Sankari Nagarajan, Tareq Hossan, Malik Alawi, Zeynab Najafova, Daniela Indenbirken, Upasana Bedi, Hanna Taipaleenmäki, Isabel Ben-Batalla, Marina Scheller, Sonja Loges, Stefan Knapp, Eric Hesse, Cheng Ming Chiang, Adam Grundhoff, Steven A. Johnsen

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

The estrogen receptor α (ERα) controls cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to control gene transcription. A deeper understanding of these transcriptional mechanisms may uncover therapeutic targets for ERα-dependent cancers. We show that BRD4 regulates ERα-induced gene expression by affecting elongation-associated phosphorylationof RNA polymerase II (RNAPII) and histone H2Bmonoubiquitination. Consistently, BRD4 activity isrequired for proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide studies revealed an enrichment of BRD4 on transcriptional start sites of active genes and a requirement of BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we demonstrate that BRD4 occupancy on distal EREs enriched for H3K27ac is required for recruitment and elongation of RNAPII on EREs and the production of ERα-dependent enhancer RNAs. These results uncover BRD4 as a central regulator of ERα function and potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)460-469
Number of pages10
JournalCell reports
Volume8
Issue number2
DOIs
StatePublished - Jul 24 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Bromodomain Protein BRD4 Is Required for Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription'. Together they form a unique fingerprint.

Cite this