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 language | English (US) |
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Pages (from-to) | 460-469 |
Number of pages | 10 |
Journal | Cell Reports |
Volume | 8 |
Issue number | 2 |
DOIs | |
State | Published - Jul 24 2014 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)