Cell Reports
Volume 8, Issue 2, 24 July 2014, Pages 460-469
Journal home page for Cell Reports

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

https://doi.org/10.1016/j.celrep.2014.06.016Get rights and content
Under a Creative Commons license
open access

Highlights

  • BRD4 regulates estrogen-induced RNAPII p-Ser2 and H2Bub1 in ER+ breast cancers

  • BRD4 occupies transcriptional start sites and EREs upon estrogen stimulation

  • BRD4 is required for estrogen-induced transcription and increased cell proliferation

  • BRD4 regulates enhancer RNA production

Summary

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 phosphorylation of RNA polymerase II (RNAPII) and histone H2B monoubiquitination. Consistently, BRD4 activity is required 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.

Cited by (0)

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).