The Arcuate Estrogenome: Estrogen Response Element-dependent and -independent Signaling of ERα
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE86609 | GEO | 2017/03/01
SECONDARY ACCESSION(S): PRJNA342400
REPOSITORIES: GEO
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Project description: Not available
| S-EPMC5460777 | biostudies-literature
Project description:To advance understanding of mechanisms leading to biological and transcriptional endpoints related to estrogen action in the mouse uterus, we have mapped ERα and RNA polymerase II binding sites using chromatin immunoprecipitation (ChIP) followed by sequencing of enriched chromatin fragments (ChIP-seq). In the absence of hormone, 5184 ERα binding sites were apparent in the vehicle treated ovariectomized uterine chromatin, while 17240 were seen one hour after estrogen (E2) treatment, indicating that some sites are occupied by unliganded ERα, and that ERα binding is increased by E2. Approximately 15% of the uterine ERα binding sites were adjacent to (<10 KB) annotated transcription start sites and many sites are found within genes or are found more than 100 KB distal from mapped genes; however, the density (sites per bp) of ERα binding sites is significantly greater adjacent to promoters. An increase in quantity of sites but no significant positional differences were seen between vehicle and E2 treated samples in the overall locations of ERα binding sites either distal from, adjacent to or within genes. Analysis of the PolII data revealed the presence of poised promoter proximal PolII on some highly upregulated genes. Additionally, co-recruitment of PolII and ERα to some distal enhancer regions was observed. A de novo motif analysis of sequences in the ERα bound chromatin confirmed that estrogen response elements (EREs) were significantly enriched. Interestingly, in areas of ERα binding without predicted ERE motifs, homeodomain transcription factor (Hox) binding motifs were significantly enriched. The integration of the ERα and PolII binding sites from our uterine ChIP-seq data with transcriptional responses revealed in our uterine microarrays has the potential to greatly enhance our understanding of mechanisms governing estrogen response in uterine and other estrogen target tissues.
2012-04-09 | GSE36455 | GEO
Project description:Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (Kiss1) neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on Kiss1 neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Here, we provide functional insight into hypothalamic estrogen sensing by analyzing estrogen receptor alpha (ERα/ESR1) DNA binding events in the arcuate and AVPV nuclei of the hypothalamus in female mice.
2023-04-25 | GSE227540 | GEO
Project description:Background: Estrogen receptor (ERα) and aryl hydrocarbon receptor (AHR) are two nuclear receptors involved in regulating gene expression. ERα and AHR are regulated by estradiol(E2) and TCDD respectively. They are also regulated by dietary ligands including 3,3´diindolylmethane (DIM) and resveratrol (RES). DIM is an ERα and AHR agonist, while RES is an ERα agonist and AHR antagonist. Few studies have investigated the impact of RES and DIM on ERα and AHR signaling at a genome-wide level. This study assessed ERα and AHR binding and associated gene expression changes after treatment of MCF-7 human breast cancer cells with DIM, RES, E2, TCDD, and E2+TCDD for 1 hour and 6 hours before ChIP and RNA sequencing respectively. Results: 88% and 86% of the ERα bound sites after RES and DIM overlapped with E2 ERα sites. RES and DIM resulted in 577 and 446 differentially expressed genes (DEGs) respectively compared to 866 after E2. 68% and 62.3% of the DEGs after RES and DIM were closest to an ERα binding site. Motif analysis indicated enrichment for AHRE motif among DIM ERα sites but not among E2 or RES ERα sites. Both DIM and E2+TCDD resulted in greater genome wide binding of AHR than TCDD. DIM and E2+TCDD resulted in 10546 and 8904 AHR and ERα co-occupied sites respectively. While co-occupied sites for both enriched for the AHR and ERE motif among others, DIM mediated co-occupied sites enriched for Tcfcp2l1, Tgif1, Gata3 motifs while E2+TCDD mediated ones enriched for the NF1 and Ppara motifs. Overlap of coregulated DEGs after DIM and E2+TCDD indicated 123 were the same among both with 81 and 85 unique coregulated DEGs respectively. Enrichment analysis indicated that more enrichment terms were different than similar for coregulated genes after E2+TCDD and DIM. Conclusions: AHR activation is responsible for DIM mediated reduced regulation of gene expression by ERα relative to E2 and only a subset of the DEG’s after DIM and RES are ERα targets indicating future studies into other transcription factors regulated by DIM and RES are needed for insights into the regulation of gene expression by these ligands.
2023-10-16 | GSE232234 | GEO
Project description:The Estrogen Receptor alpha (ERα) controls key cellular functions in hormone responsive breast cancer by assembling in large functional multiprotein complexes. ERα ligands are classified as agonists and antagonist, according to the response they elicit, thus the molecular characterization of the of ERα nuclear iteractome composition following estrogen and antiestrogen stimulation whose is needed to understand their effects on estrogen target tissues, in particular breast cancer. To this aim interaction proteomics coupled to mass spectrometry (MS) was applied to map the ERα nuclear interacting partners in MCF7 breast cancer cell nuclei following estrogen and antiestrogen stimuli.
2020-09-02 | PXD018709 | Pride
Project description:To understand how chronic cadmium exposure alters the dependency of ERα in terms of gene expression, we transiently silenced ERα using ICI, an antiestrogen that promotes the degradation of ERα. MCF7 and cadmium-adapted cells (Cd7 and Cd12) were treated with ICI to mediate the degradation of ERα, and a nonbiased global gene expression analysis was conducted using RNA-seq. MCF7 shared 67.3% and 59.5% of the DE genes with Cd7 and Cd12 cells, respectively, suggesting that ERα continues to play an important role in regulating the expression of genes following chronic cadmium exposure. 138 ERE genes (76.7%) were shared by all three cell lines, in that expression changed in the same direction (either up- or downregulated). For the estrogen-responsive genes, 428 (53.6%) of the 799 genes were altered in the same direction in all three cell lines. These findings show that while a majority of ERE genes responded in the same manner to loss of ERα, more variability existed within the estrogen-responsive genes. Collectively, these results indicate that while chronic cadmium exposure leads to genome-wide transcriptional changes, ERα remains important for regulating the expression of genes and maintaining the malignant phenotypes associated with breast cancer progression.
2019-08-21 | GSE134127 | GEO
Project description:To better understand the role of SRC-1 in estrogen signaling in bone, a genome-wide analysis of ERα and SRC-1 binding sites in the absense and presence of E2 was conducted.
2016-12-04 | GSE26110 | GEO
Project description:ChIP-seq from mice with DNA binding mutations in Esr1 (KIKO mouse). Estrogen Receptor α (ERα) interacts with DNA, directly, or indirectly via other transcription factors, referred to as “tethering”. Evidence for tethering is based on in vitro studies and a widely used “KIKO” mouse model containing mutations that prevent direct estrogen response element (ERE) DNA-binding. KIKO mice are infertile, due in part to the inability of estrogen (E2) to induce uterine epithelial proliferation. To elucidate the molecular events that prevent KIKO uterine growth, regulation of the pro-proliferative E2 target gene Klf4, and of Klf15, a progesterone (P4) target gene that opposes KLF4’s pro-proliferative activity, were evaluated. Klf4 induction was impaired in KIKO uteri; however, Klf15 was induced by E2 rather than by P4. Whole uterine ChIP-seq revealed enrichment of KIKO ERα binding to hormone response elements (HRE), motifs. KIKO binding to HRE motifs was verified using reporter gene and DNA-binding assays. Because the KIKO ERα has HRE DNA-binding activity, we evaluated the “EAAE” ERα, which has more severe DBD mutations, and demonstrated lack of ERE or HRE reporter gene induction or DNA binding. The EAAE mouse has an ERα-null like phenotype, with impaired uterine growth and transcriptional activity. Our findings demonstrate that the KIKO mouse model, which has been used by numerous investigators, cannot be used to establish biological functions for ERα tethering, as KIKO ERα effectively stimulates transcription using HRE motifs. The EAAE-ERα DBD mutant mouse demonstrates that ERα DNA-binding is crucial for biological and transcriptional processes in reproductive tissues, and that ERα-tethering may not contribute to estrogen-responsiveness in vivo.
2014-04-03 | GSE56466 | GEO
Project description:The nuclear receptor, estrogen receptor alpha (ERα), controls the expression of hundreds of genes responsible for target cell phenotypic properties, but the relative importance of direct vs. tethering mechanisms of DNA binding has not been established. In this first report, we examine the genome-wide chromatin localization of an altered-specificity mutant ER with a DNA-binding domain deficient in binding to estrogen response element (ERE)-containing DNA (DBDmut ER) vs. wild type ERα. Using high-throughput sequencing of ER chromatin immunoprecipitations (ChIP-Seq) and mRNA transcriptional profiling, we show that direct ERE binding is required for most (75%) estrogen-dependent gene regulation and 90% of hormone-dependent recruitment of ER to genomic binding sites. De novo motif analysis of the chromatin binding regions in MDA-MB-231 human breast cancer cells defined unique transcription factor profiles responsible for genes regulated through tethering vs. direct DNA (ERE) binding, with Runx motifs enriched in ER-tethered sites. We confirmed a role for Runx1 in mediating ERa genomic recruitment and regulation of tethering genes. Our findings delineate the contributions of ERE binding vs. binding through response elements for other transcription factors in chromatin localization and ER-dependent gene regulation, paradigms likely to underlie the gene regulatory actions of other nuclear receptors as well. This SuperSeries is composed of the following subset Series: GSE22593: WT and DBDmut Breast Cancer Cells GSE22609: Genome-Wide Maps of WT and DBDmut Estrogen Receptor in Human Breast Cancer Cells Refer to individual Series
2010-06-29 | E-GEOD-22610 | biostudies-arrayexpress
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.
2019-09-25 | GSE109570 | GEO