Distinct properties of cell type-specific and shared transcription factor binding sites
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE49993 | GEO | 2013/12/31
SECONDARY ACCESSION(S): PRJNA215762
REPOSITORIES: GEO
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Project description:Most human transcription factors bind a small subset of potential genomic sites and often use different subsets in different cell types. To identify mechanisms that govern cell type-specific transcription factor binding, we used an integrative approach to study estrogen receptor α (ER). We found that ER exhibits two distinct modes of binding. Shared sites, bound in multiple cell types, are characterized by high affinity estrogen response elements (EREs), inaccessible chromatin and a lack of DNA methylation, while cell-specific sites are characterized by a lack of EREs, co-occurrence with other transcription factors and cell type-specific chromatin accessibility and DNA methylation. These observations enabled accurate quantitative models of ER binding that suggest tethering of ER to one-third of cell-specific sites. The distinct properties of cell-specific binding were also observed with glucocorticoid receptor and for ER in primary mouse tissues, representing an elegant genomic encoding scheme for generating cell type-specific gene regulation. ChIP-seq of transcription factors in mouse tissues
2013-12-31 | E-GEOD-49993 | biostudies-arrayexpress
Project description:Estrogens are steroid hormones that play critical roles in the initiation, development, and metastasis of breast and uterine cancers. The estrogen (E2) response in breast cancer cells is predominantly mediated by the estrogen receptor-alpha (ER alpha), a ligand-activated transcription factor. ER alpha regulates transcription of target genes through direct binding to its cognate recognition sites, known as estrogen response elements (EREs), or by modulating the activity of other DNA-bound transcription factors at alternative DNA sequences. The proto-oncogene c-myc is upregulated by ER¦à in response to E2 and encodes a transcription factor, c-MYC, which regulates a cascade of gene targets whose products mediate cellular transformation. This study aims at mapping the binding sites of these two transcription factors (ER alpha and c-MYC) in one ER alpha positive breast cancer cell line (MCF7 cell line). Keywords: ChIP-Chip Analysis This series contains ChIP-on-Chip data sets for two transcription factors (ER alpha and c-MYC) and control samples (INPUT). All the experiments are done in triplicates. MCF7 Cells were E2-deprived for 3 days and then were treated with 10 nM E2 (45 minutes and 2 hours for mapping ER alpha and c-MYC binding sites, respectively) at 80% confluence.
2010-05-26 | E-GEOD-10800 | biostudies-arrayexpress
Project description:Estrogens are steroid hormones that play critical roles in the initiation, development, and metastasis of breast and uterine cancers. The estrogen (E2) response in breast cancer cells is predominantly mediated by the estrogen receptor-alpha (ER alpha), a ligand-activated transcription factor. ER alpha regulates transcription of target genes through direct binding to its cognate recognition sites, known as estrogen response elements (EREs), or by modulating the activity of other DNA-bound transcription factors at alternative DNA sequences. The proto-oncogene c-myc is upregulated by ER¦Á in response to E2 and encodes a transcription factor, c-MYC, which regulates a cascade of gene targets whose products mediate cellular transformation. This study aims at mapping the binding sites of these two transcription factors (ER alpha and c-MYC) in one ER alpha positive breast cancer cell line (MCF7 cell line). Keywords: ChIP-Chip Analysis
2008-03-13 | GSE10800 | GEO
Project description:The human genome encodes an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by the combined action of multiple enhancers. We have previously shown that neighboring estrogen-responsive enhancers, which are approximately 5,000 basepairs apart, exhibit complex synergistic contributions to the production of an estrogenic transcriptional response. Here we sought to determine the molecular underpinnings of the observed enhancer cooperativity. We generated genetic deletions of individual estrogen receptor (ER) bound enhancers and found that enhancers containing full estrogen response element (ERE) motifs control ER binding at neighboring sites, while enhancers with pre-existing histone acetylation/accessibility confer a permissible chromatin environment to the neighboring enhancers. Genome engineering revealed that a cluster of two enhancers with half EREs could not compensate for the lack of a full ERE site within the cluster. In contrast, two enhancers with full EREs produced a transcriptional response greater than the wild-type locus. By swapping genomic sequences between enhancers, we found that the genomic location in which a full ERE resides strongly influences enhancer activity. Our results lead to a model in which a full ERE is required for ER recruitment, but the presence of pre-existing histone acetylation within an enhancer cluster is also needed in order for estrogen-driven gene regulation to occur.
2020-03-18 | GSE147141 | GEO
Project description:The human genome encodes an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by the combined action of multiple enhancers. We have previously shown that neighboring estrogen-responsive enhancers, which are approximately 5,000 basepairs apart, exhibit complex synergistic contributions to the production of an estrogenic transcriptional response. Here we sought to determine the molecular underpinnings of the observed enhancer cooperativity. We generated genetic deletions of individual estrogen receptor (ER) bound enhancers and found that enhancers containing full estrogen response element (ERE) motifs control ER binding at neighboring sites, while enhancers with pre-existing histone acetylation/accessibility confer a permissible chromatin environment to the neighboring enhancers. Genome engineering revealed that a cluster of two enhancers with half EREs could not compensate for the lack of a full ERE site within the cluster. In contrast, two enhancers with full EREs produced a transcriptional response greater than the wild-type locus. By swapping genomic sequences between enhancers, we found that the genomic location in which a full ERE resides strongly influences enhancer activity. Our results lead to a model in which a full ERE is required for ER recruitment, but the presence of pre-existing histone acetylation within an enhancer cluster is also needed in order for estrogen-driven gene regulation to occur.
2020-03-18 | GSE147140 | GEO
Project description:We explored the combinatorial interactions between p53, estrogen receptors and NFkB using the breast adenocarcinoma-derived MCF7 cells. Recently, we have established that p53 can modulate transcription also through non-canonical response elements (REs), consisting of half-sites and ¾ sites. In particular, we identified a half-site p53 response element in the promoter of FLT1/VEGFR-I gene that was required but not sufficient for the p53 responsiveness of the promoter. The transcriptional control required also estrogen receptor (ER) half-sites (EREs) located in close proximity to the p53 RE. Further studies led us to establish that p53-mediated transcription from the FLT1 half site RE is dependent on ER binding at the EREs and strongly influenced by the level of ER proteins, and the specific nature of the p53-inducing stress as well as ER ligand. In another study we found an enrichment of NFkB REs nearby p53 REs in p53 target genes, suggesting an additional mode of functional interactions between these two transcription factors. To identify at a genome scale the transcriptional network that selectively responds to the concomitant activation of p53, ER and/or NFkB, we measured gene expression upon treatment with specific chemotherapeutic agents combined with 17-β estradiol (E2) and/or the inflammatory cytokine TNFα. Firstly we measured using MCF7 cells growing in estrogen-depleted media the transcriptome changes induced by doxorubicin (doxo) and 5-fluorouracil (5FU), two different drugs both able to stabilize and activate the p53 protein. We next obtained the expression profiles in the presence of E2 with or without doxo or 5FU. We also measured transcriptome changes in response to TNFαalone or in combination with doxo and/or E2. All these analyses were conducted using the same batch of MCF7 cells (wild type for p53, ERα, ERβ -weakly-, and NFkB positive) that we had previously used to characterize the cis-mediated transcriptional cooperation between p53 and ER at the FLT1 gene. Keywords: transcription factor, transcriptional networks, p53, ER, NFkB, p53-ER-NFkB crosstalk, doxorubicin, 5-fluorouracil, 17-β estradiol, TNFα, combined genotoxic, estrogenic and inflammatory responses, composite DNA binding site signatures, MCF7. The cooperation at the transcriptional level among p53, ERs and NFkB was analyzed by transcriptome analysis in response to different stimuli (doxo or 5FU, E2, TNFα). To identify mRNA molecules that would be modulated by the coordinated activity of the three TFs, gene expression signals derived from the combinatorial treatment were compared by microarrays analyses to those obtained from each drug when individually administered. Total RNA was isolated from MCF7 cells grown in estrogen-depleted medium and treated so as to stimulate the activity of the three different transcription factors (p53, ERs and NFkB). Cells lysates were collected after 10 hours from the treatments. All experiments were run from triplicate to septuples.
2011-06-01 | E-GEOD-24065 | biostudies-arrayexpress
Project description:TRIM24 PHD-Bromo domains exhibit preferential binding to unmethylated H3K4 and acetylated H3K27. TRIM24 is a co-activator of estrogen receptor (ER). The results suggest that specific ER-binding sites are depleted of H3K4me2 with estrogen treatment. TRIM24 binds these sites preferentially and facilitates ER-regulated gene expression, cell survival and proliferation.
2010-09-17 | GSE24166 | GEO
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
Project description:We explored the combinatorial interactions between p53, estrogen receptors and NFkB using the breast adenocarcinoma-derived MCF7 cells. Recently, we have established that p53 can modulate transcription also through non-canonical response elements (REs), consisting of half-sites and ¾ sites. In particular, we identified a half-site p53 response element in the promoter of FLT1/VEGFR-I gene that was required but not sufficient for the p53 responsiveness of the promoter. The transcriptional control required also estrogen receptor (ER) half-sites (EREs) located in close proximity to the p53 RE. Further studies led us to establish that p53-mediated transcription from the FLT1 half site RE is dependent on ER binding at the EREs and strongly influenced by the level of ER proteins, and the specific nature of the p53-inducing stress as well as ER ligand. In another study we found an enrichment of NFkB REs nearby p53 REs in p53 target genes, suggesting an additional mode of functional interactions between these two transcription factors. To identify at a genome scale the transcriptional network that selectively responds to the concomitant activation of p53, ER and/or NFkB, we measured gene expression upon treatment with specific chemotherapeutic agents combined with 17-β estradiol (E2) and/or the inflammatory cytokine TNFα. Firstly we measured using MCF7 cells growing in estrogen-depleted media the transcriptome changes induced by doxorubicin (doxo) and 5-fluorouracil (5FU), two different drugs both able to stabilize and activate the p53 protein. We next obtained the expression profiles in the presence of E2 with or without doxo or 5FU. We also measured transcriptome changes in response to TNFα alone or in combination with doxo and/or E2. All these analyses were conducted using the same batch of MCF7 cells (wild type for p53, ERα, ERβ -weakly-, and NFkB positive) that we had previously used to characterize the cis-mediated transcriptional cooperation between p53 and ER at the FLT1 gene. Keywords: transcription factor, transcriptional networks, p53, ER, NFkB, p53-ER-NFkB crosstalk, doxorubicin, 5-fluorouracil, 17-β estradiol, TNFα, combined genotoxic, estrogenic and inflammatory responses, composite DNA binding site signatures, MCF7.
2011-06-01 | GSE24065 | GEO
Project description:TRIM24 PHD-Bromo domains exhibit preferential binding to unmethylated H3K4 and acetylated H3K27. TRIM24 is a co-activator of estrogen receptor (ER). The results suggest that specific ER-binding sites are depleted of H3K4me2 with estrogen treatment. TRIM24 binds these sites preferentially and facilitates ER-regulated gene expression, cell survival and proliferation. ChIP performed on MCF7 cells +/- estrogen with antibodies against ER, TRIM24 and H3K4me2. ChIP assays of ER, co-activator TRIM24 and H3K4me2 were performed with two concentrations of antibody, without and 6h with estrogen treatment of MCF7 cells. Antibody-enriched samples were sequenced two times, and compared to an IgG negative control and Input. Enriched DNA sequenced by Illumina Solexa.
2010-09-17 | E-GEOD-24166 | biostudies-arrayexpress