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Genome-wide activity of unliganded Estrogen Receptor alpha in breast cancer cells [ChIP-Seq]

ABSTRACT: Estrogen Receptor α (ERα) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ERα has functions which are independent of ligands. In the present work, we investigated the binding of ERα to chromatin in absence of ligands, and its function(s) on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ERα binds to more than four thousands chromatin sites. Unexpectedly, although almost entirely comprised in the larger group of estrogen-induced binding sites, we found that unliganded-ERα binding is specifically linked to genes with developmental functions, as compared to estrogen-induced binding. Moreover, we found that siRNA-mediated downregulation of ERα in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Downregulated mRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ERα downregulation using shRNA, which caused cell-growth arrest, was accompanied by increased H3K27me3 at ERα binding sites. Finally, we found that FOXA1 and AP2γ binding to several sites is decreased upon ERα silencing, suggesting that unliganded ERα participates, together with other factors, to the maintenance of the luminal-specific cistrome in breast cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53531 | GEO | 2014/03/03

SECONDARY ACCESSION(S): PRJNA232304

REPOSITORIES: GEO

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Genome-wide activity of unliganded Estrogen Receptor alpha in breast cancer cells [RNA-Seq]

Project description:ERα is essential for the anti-proliferative response of breast cancer cells not only to estrogen antagonists, but also to estrogen withdrawal by means of aromatase inhibitors. We explored here one of the simplest explanation for this, consisting in the possibility that ERα may have a wide genomic function in absence of ligands. The genomic binding of ERα in the complete absence of estrogen was then studied using hormone-dependent MCF7 cells, by chromatin immunoprecipitation sequencing. From these data, 4.2K highly significant binding events were identified, which were further confirmed by comparing binding events in cells expressing ERα to cells silenced for ERα. Apo-ERα binding sites were distributed close to genes with functions associated to cell growth and epithelial maintenance and show significant overlap with binding of other transcription factors important for luminal epithelial breast cancer. Interestingly, we found that upon ERα silencing cognate gene transcription in absence of estrogen is downregulated and this is accompanied by increased H27Kme3 at ERα binding sites. RNA-Seq experiments showed that unliganded ERα controls basal transcription widely, including both coding and noncoding transcripts. Genes affected by ERα silencing can be easily functionally related to mammary epithelium differentiation and maintenance, especially when considering downregulated genes. Additional functions related to inflammatory and immune response was observed. Our data unravel unexpected actions of ERα in breast cancer cells and provide a novel framework to understand success and failure of hormone therapy in breast cancer. Examination of unligandend estrogen receptor alpha (aERα) DNA interactions in control and aERα siRNA treated MCF7 cells.

2014-03-03 | E-GEOD-53532 | biostudies-arrayexpress

Genome-wide activity of unliganded Estrogen Receptor alpha in breast cancer cells [ChIP-Seq]

Project description:Estrogen Receptor ? (ER?) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ER? has functions which are independent of ligands. In the present work, we investigated the binding of ER? to chromatin in absence of ligands, and its function(s) on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ER? binds to more than four thousands chromatin sites. Unexpectedly, although almost entirely comprised in the larger group of estrogen-induced binding sites, we found that unliganded-ER? binding is specifically linked to genes with developmental functions, as compared to estrogen-induced binding. Moreover, we found that siRNA-mediated downregulation of ER? in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Downregulated mRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ER? downregulation using shRNA, which caused cell-growth arrest, was accompanied by increased H3K27me3 at ER? binding sites. Finally, we found that FOXA1 and AP2? binding to several sites is decreased upon ER? silencing, suggesting that unliganded ER? participates, together with other factors, to the maintenance of the luminal-specific cistrome in breast cancer cells. Examination of unligandend estrogen receptor alpha (apoER?) DNA interactions in control and ER? siRNA treated MCF7 cells.

2014-03-03 | E-GEOD-53531 | biostudies-arrayexpress

Genome-wide activity of unliganded Estrogen Receptor alpha in breast cancer cells [RNA-Seq]

2014-03-03 | GSE53532 | GEO

Identification of cytoplasmic proteins interacting with unliganded estrogen receptor α and β- in human breast cancer cells

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2015-03-11 | PXD001202 | Pride

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2016-11-22 | GSE51535 | GEO

Nuclear Estrogen Receptor alpha (ERα) interactome following estrogen and antiestrogen treatment.

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.

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Unliganded Estrogen Receptor beta (ERβ) interactome before and after RNAse treatment in human breast cancer cells nuclei.

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ERα and PolII ChIP seq from Mouse Uterus

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

Co-regulated gene expression by estrogen receptor-α and liver receptor homolog-1 is a feature of the estrogen response in breast cancer cells

Project description:Estrogen receptor α (ERα) is a nuclear receptor that is the driving transcription factor expressed in the majority of breast cancers. Recent studies have demonstrated that the liver receptor homolog-1 (LRH-1), another nuclear receptor, is ERα-regulated in breast cancer cells. Further, LRH-1 stimulates proliferation and promotes motility and invasion of breast cancer cells. To determine the mechanisms of LRH-1 action in breast cancer cells, we carried out gene expression microarray analysis following siRNA-mediated LRH-1 knockdown. Interestingly, gene ontology (GO) category enrichment analysis of the genes differentially regulated in the presence or absence of LRH-1 identified estrogen responsive genes as the most highly enriched GO categories. To further define LRH-1 target genes, we performed chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) to identify genomic targets of LRH-1. Remarkably, ChIP-seq showed LRH-1 binding at many ERα binding sites. Analysis of select binding sites confirmed regulation of ERα-regulated genes by LRH-1 through binding to estrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 over-expression stimulated ERα recruitment, whilst LRH-1 knockdown reduced ERα recruitment to ERα binding sites. Taken together, our findings establish a key role for LRH-1 in the regulation of ERα target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH-1 and ERα at estrogen response elements controls the expression of estrogen-responsive genes.

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