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

87 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)

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    Nagarajan, S., Hossan, T., Alawi, M., Najafova, Z., Indenbirken, D., Bedi, U., Taipaleenmäki, H., Ben-Batalla, I., Scheller, M., Loges, S., Knapp, S., Hesse, E., Chiang, C. M., Grundhoff, A., & Johnsen, S. A. (2014). Bromodomain Protein BRD4 Is Required for Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription. Cell Reports, 8(2), 460-469. https://doi.org/10.1016/j.celrep.2014.06.016