Genome-wide analysis of SRC-1/NCOA1 and Erα/ESR1 binding in chromatin obtained from the ERα stably transfected U2OS osteosarcoma cell line (U2OS-ERα) with ChIP-SEQ.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE26110 | GEO | 2016/12/04
SECONDARY ACCESSION(S): PRJNA135189
REPOSITORIES: GEO
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Project description:Estrogen receptors alpha (ERα) converges estrogen signaling by orchestrating estrogen (E2)-dependent transcription regulation. Upon binding to the chromatin, ERα serves as a nucleation site for de novo formation of transcription enhancer complexes. Steroid receptor coactivators family proteins (SRCs, a.k.a p160) and Mediator complex are the two coregulators for ERα that directly interact with the receptors and control enhancer activity by regulating recruitment of other coregulators and transcription machinery. Lysine acetyltransferase p300/CBP is also a critical coregulator for ERα that is recruited through SRCs in stable ERα enhancer complex. ERα enhancers exhibit common enhancer features including enrichment of enhancer-specific histone modification (e.g. H3K4me1 and H3K27ac), coregulator recruitment, and active transcription. Despite of recognition of those enhancer characteristics, the order of assembly and functions and the functional relationships among enhancer features during active enhancer complex formation is not well understood. Using the time course genomics and molecular biology assays, we dissect the order of assembly and functions of ERα enhancer complex formation. We describe the mechanism of SRC-independent p300 recruitment mediated by Mediator, leading to initial partial activation of the ERα enhancer for enhance priming. Maturation of the enhancer in turn switches the p300 recruitment mechanism to an SRC-dependent manner, resulting in the maximum enhancer activity and transcription outcomes. Thus, our results illustrate the role of SRC in enhancing the activity of primed enhancers. Furthermore, we show that forced recruitment of p300 to inactive enhancers establishes active enhancer marks and induces ERα-target gene expression. Together, we demonstrate the molecular mechanisms of ERα enhancer complex formation where p300 plays a pivotal role in enhancer activation and target gene expression controlled by distinctive mechanisms through different stages of ERα enhancer complex formation.
2018-05-21 | GSE95122 | GEO
Project description:Estrogen receptors alpha (ERα) converges estrogen signaling by orchestrating estrogen (E2)-dependent transcription regulation. Upon binding to the chromatin, ERα serves as a nucleation site for de novo formation of transcription enhancer complexes. Steroid receptor coactivators family proteins (SRCs, a.k.a p160) and Mediator complex are the two coregulators for ERα that directly interact with the receptors and control enhancer activity by regulating recruitment of other coregulators and transcription machinery. Lysine acetyltransferase p300/CBP is also a critical coregulator for ERα that is recruited through SRCs in stable ERα enhancer complex. ERα enhancers exhibit common enhancer features including enrichment of enhancer-specific histone modification (e.g. H3K4me1 and H3K27ac), coregulator recruitment, and active transcription. Despite of recognition of those enhancer characteristics, the order of assembly and functions and the functional relationships among enhancer features during active enhancer complex formation is not well understood. Using the time course genomics and molecular biology assays, we dissect the order of assembly and functions of ERα enhancer complex formation. We describe the mechanism of SRC-independent p300 recruitment mediated by Mediator, leading to initial partial activation of the ERα enhancer for enhance priming. Maturation of the enhancer in turn switches the p300 recruitment mechanism to an SRC-dependent manner, resulting in the maximum enhancer activity and transcription outcomes. Thus, our results illustrate the role of SRC in enhancing the activity of primed enhancers. Furthermore, we show that forced recruitment of p300 to inactive enhancers establishes active enhancer marks and induces ERα-target gene expression. Together, we demonstrate the molecular mechanisms of ERα enhancer complex formation where p300 plays a pivotal role in enhancer activation and target gene expression controlled by distinctive mechanisms through different stages of ERα enhancer complex formation.
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Project description:Estrogen Receptor alpha (ERα), a nuclear receptor with transcriptional activity, is a master regulator of estrogen signaling, widely known as therapeutic target in hormone-responsive breast cancer (BC). Moreover, ERα is highly expressed in approximately 80% of High Grade Serous Ovarian Cancer (HGSOC), the most common epithelial ovarian carcinoma. Despite some promising clinical trials evaluating endocrine therapy in this type of tumor, the role of ERα is still unknown. Epigenetic changes, such as DNA methylation, are emerging as key contributing factors to carcinogenesis. Disruptor of telomeric silencing-1-like (DOT1L), the only known histone methyl transferase capable to produce H3K79 mono, di and tri-methylation, modulates ERα actions in hormone-responsive BC. Considering this evidence, ERα-DOT1L association was confirmed in ERα-positive OC cells, PEO1 and PEO4, by Co-IP. DOT1L pharmacological inhibition by EPZ004777 (EPZ) revealed the involvement of this epigenetic enzyme in cell proliferation, cell cycle progression and apoptosis. Transcriptome profiling after ICI (a Selective Estrogen Receptor Degrader) and EPZ treatment, in both cell lines, has underlined a deep impact of both compounds on ERα-modulated genes, including the down-regulation of ERα itself. On the other hand, functional analysis showed that commonly affected transcripts are involved in different cellular processes, such as cancer cell survival, chemoresistance and cell cycle progression. Moreover, ChIP-qPCR performed on ERα promoter highlighted ERα and DOT1L co-localization, both in PEO1 and in PEO4 cells, which was reduced after EPZ treatment, suggesting a role of this complex on receptor transcriptional activity. In addition, drug combination studies performed with EPZ and ICI showed an additive effect in cell growth inhibition. Taken together, these results suggest DOT1L as a potential therapeutic target in the treatment of OC.
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Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
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Project description:Experimental aim: identification of SRC-2 and SRC-3-related genes in MCF-7 breast cancer cells. Experimental workflow: 1. shRNA transduction. MCF-7 cells were transduced with a mix of lentiviral particles containing five individual lentiviral pLKO.1-puro short hairpin (sh) RNA plasmids targeting different sequences on SRC-2 or SRC-3 mRNA and a pLKO.1-puro empty vector control. The puromycin selections were maintained for three weeks to obtain cells containing stably integrated shRNA. 2. Sample preparation. RNA was extracted from eight independent replicates expressing the pLKO.1-puro empty shRNA vector (shKTR), from eight replicates of SRC-2 shRNA expressing cells (shSRC-2), and from seven replicates of SRC-3 shRNA expressing cells (shSRC-3). 300 ng of total RNA from each cell sample was biotin-labelled and amplified.
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