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Distinct roles of BET Family Members in ERα Enhancer Function and Gene Regulation in Breast Cancer Cells [ChIP-seq]

ABSTRACT: Estrogen (E2)-dependent gene regulation mediated by estrogen receptor alpha (ERα) plays a mitogenic role in ER-positive breast cancer cells. Although clinical applications of selective estrogen receptor modulators (SERMs), which directly interact with ERα to alter ERα activity, have been effective as a first line of treatment for breast cancer patients, a large subset of the patients will develop resistance after prolonged use of SERMs. Thus, there is a great need to develop alternative therapeutic strategies for SERM-resistant breast cancers. Here, we describe the potential use of the bromodomain family member protein (BRD) selective bromodomain inhibitor, JQ1, to alter E2-dependent gene expression program and inhibit E2-dependent growth of breast cancer cells. We show that each family member has partially redundant roles as ERα coregulators that are required for ERα-mediated gene transcription. Furthermore, we demonstrate the function of BRD3 as a molecular sensor of total BRD activity by the compensatory control of its protein levels. In addition, BRD3 colocalizes with a subset of ERα binding sites (ERBSs) that are enriched for active enhancer features and associated with highly E2-induced genes. Collectively, we illustrate a critical role of the BET family members in ERα dependent gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109571 | GEO | 2019/09/25

REPOSITORIES: GEO

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Distinct Roles of BET Family Members in ERα Enhancer Function and Gene Regulation in Breast Cancer Cells [RNA-seq]

Project description:Estrogen (E2)-dependent gene regulation mediated by estrogen receptor alpha (ERα) plays a mitogenic role in ER-positive breast cancer cells. Although clinical applications of selective estrogen receptor modulators (SERMs), which directly interact with ERα to alter ERα activity, have been effective as a first line of treatment for breast cancer patients, a large subset of the patients will develop resistance after prolonged use of SERMs. Thus, there is a great need to develop alternative therapeutic strategies for SERM-resistant breast cancers. Here, we describe the potential use of the bromodomain family member protein (BRD) selective bromodomain inhibitor, JQ1, to alter E2-dependent gene expression program and inhibit E2-dependent growth of breast cancer cells. We show that each family member has partially redundant roles as ERα coregulators that are required for ERα-mediated gene transcription. Furthermore, we demonstrate the function of BRD3 as a molecular sensor of total BRD activity by the compensatory control of its protein levels. In addition, BRD3 colocalizes with a subset of ERα binding sites (ERBSs) that are enriched for active enhancer features and associated with highly E2-induced genes. Collectively, we illustrate a critical role of the BET family members in ERα dependent gene expression.

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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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