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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.

Original publication

DOI

10.1016/j.celrep.2014.06.016

Type

Journal article

Journal

Cell Rep

Publication Date

24/07/2014

Volume

8

Pages

460 - 469

Keywords

Animals, Breast Neoplasms, Cell Proliferation, Endometrial Neoplasms, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Histones, MCF-7 Cells, Mice, Mice, Inbred C57BL, Nuclear Proteins, RNA Polymerase II, Response Elements, Transcription Factors, Transcriptional Activation