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Bromodomain protein BRD4 is required for estrogen receptor-dependent transcription and enhancer activation [ChIP-seq]

ABSTRACT: The estrogen receptor-α (ERα) is a transcription factor which plays a critical role in controlling cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to induce or repress gene transcription. A deeper understanding of these transcriptional mechanisms may uncover novel therapeutic targets for ERα-dependent cancers. Here we show for the first time that BRD4 regulates ERα−induced gene expression by affecting elongation-associated phosphorylation of RNA Polymerase II (RNAPII P-Ser2) and histone H2B monoubiquitination (H2Bub1). Consistently, BRD4 activity is required for estrogen-induced proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide occupancy studies revealed an enrichment of BRD4 on transcriptional start sites as well as EREs enriched for H3K27ac and demonstrate a requirement for BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we further demonstrate that BRD4 occupancy correlates with active mRNA transcription and is required for the production of ERα-dependent enhancer RNAs (eRNAs). These results uncover BRD4 as a central regulator of ERα function and potential therapeutic target. ChIP-sequencing of BRD4, ERα and H2Bub1 in MCF7 cells treated with +/- estrogen treatment and or +/- JQ1 treatment in triplicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Steven Johnsen

PROVIDER: E-GEOD-55921 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Bromodomain protein BRD4 is required for estrogen receptor-dependent transcription and enhancer activation [RNA-Seq]

Project description:The estrogen receptor-M-NM-1 (ERM-NM-1) is a transcription factor which plays a critical role in controlling cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to induce or repress gene transcription. A deeper understanding of these transcriptional mechanisms may uncover novel therapeutic targets for ERM-NM-1-dependent cancers. Here we show for the first time that BRD4 regulates ERM-NM-1M-bM-^HM-^Rinduced gene expression by affecting elongation-associated phosphorylation of RNA Polymerase II (RNAPII P-Ser2) and histone H2B monoubiquitination (H2Bub1). Consistently, BRD4 activity is required for estrogen-induced proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide occupancy studies revealed an enrichment of BRD4 on transcriptional start sites as well as EREs enriched for H3K27ac and demonstrate a requirement for BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we further demonstrate that BRD4 occupancy correlates with active mRNA transcription and is required for the production of ERM-NM-1-dependent enhancer RNAs (eRNAs). These results uncover BRD4 as a central regulator of ERM-NM-1 function and potential therapeutic target. mRNA expression profiles of MCF7 cells treated with +/- estrogen treatment under negative control siRNA, BRD4 siRNA or JQ1 treatment, in duplicates.

2014-07-10 | E-GEOD-55922 | biostudies-arrayexpress

Bromodomain protein BRD4 is required for estrogen receptor-dependent transcription and enhancer activation [ChIP-seq]

Project description:The estrogen receptor-α (ERα) is a transcription factor which plays a critical role in controlling cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to induce or repress gene transcription. A deeper understanding of these transcriptional mechanisms may uncover novel therapeutic targets for ERα-dependent cancers. Here we show for the first time that BRD4 regulates ERα−induced gene expression by affecting elongation-associated phosphorylation of RNA Polymerase II (RNAPII P-Ser2) and histone H2B monoubiquitination (H2Bub1). Consistently, BRD4 activity is required for estrogen-induced proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide occupancy studies revealed an enrichment of BRD4 on transcriptional start sites as well as EREs enriched for H3K27ac and demonstrate a requirement for BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we further demonstrate that BRD4 occupancy correlates with active mRNA transcription and is required for the production of ERα-dependent enhancer RNAs (eRNAs). These results uncover BRD4 as a central regulator of ERα function and potential therapeutic target.

2014-07-10 | GSE55921 | GEO

Bromodomain protein BRD4 is required for estrogen receptor-dependent transcription and enhancer activation [RNA-Seq]

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H4K12ac is regulated by estrogen receptor-alpha and is associated with BRD4 function and inducible transcription

Project description:Hormone-dependent gene expression requires dynamic and coordinated epigenetic changes. Estrogen receptor-positive (ER+) breast cancer is particularly dependent upon extensive chromatin remodeling and changes in histone modifications for the induction of hormone-responsive gene expression. Our previous studies established an important role of bromodomain-containing protein-4 (BRD4) in promoting estrogen-regulated transcription and proliferation of ER+ breast cancer cells. Here, we investigated the association between genome-wide occupancy of histone H4 acetylation at lysine 12 (H4K12ac) and BRD4 in the context of estrogen-induced transcription. Similar to BRD4, we observed that H4K12ac occupancy increases near the transcription start sites (TSS) of estrogen-induced genes as well as at distal ERα binding sites in an estrogen-dependent manner. Interestingly, H4K12ac occupancy highly correlates with BRD4 binding and enhancer RNA production on ERα-positive enhancers. Consistent with an importance in estrogen-induced gene transcription, H4K12ac occupancy globally increased in ER-positive cells relative to ER-negative cells and these levels were further increased by estrogen treatment in an ERα-dependent manner. Together, these findings reveal a strong correlation between H4K12ac and BRD4 occupancy with estrogen-dependent gene transcription and further suggest that modulators of H4K12ac and BRD4 may serve as new therapeutic targets for hormone-dependent cancers. ChIP-seq profiles of H4K12ac in MCF7 cells treated with +/- estrogen treatment and MCF10A cells.

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2020-07-13 | GSE146645 | GEO

H4K12ac is regulated by estrogen receptor-alpha and is associated with BRD4 function and inducible transcription

2015-05-02 | GSE65886 | GEO

The SET Oncoprotein Promotes Estrogen-Induced Transcription by Facilitating Establishment of Active Chromatin

Project description:SET is a multifunctional histone-binding oncoprotein that regulates transcription by an unclear mechanism. Here, we show that SET enhances estrogen-dependent transcription. SET knockdown abrogates transcription of estrogen-responsive genes and their enhancer RNAs (eRNAs). In response to 17β-estradiol (E2), SET binds to the estrogen receptor α (ERα) and is recruited to estrogen receptor α (ERα)-bound enhancers and promoters at estrogen response elements (EREs). SET functions as a histone H2 chaperone that dynamically associates with H2A.Z via its acidic C-terminal domain and promotes H2A.Z incorporation, ERα, MLL1 and KDM3A loading and modulates histone methylation at EREs. SET depletion diminishes recruitment of condensin complexes to EREs and impairs E2-dependent enhancer-promoter looping. Thus, SET boosts E2-induced gene expression by establishing an active chromatin structure at ERα-bound enhancers and promoters, which is essential for transcriptional activation.

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The SET Oncoprotein Promotes Estrogen-Induced Transcription by Facilitating Establishment of Active Chromatin

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Centromeric H2B monoubiquitination promotes noncoding transcription and chromatin integrity

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The Histone H2B Monoubiquitination Regulatory Pathway is Required for Differentiation of Multipotent Stem Cells

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