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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Cohesin is required for expression of the estrogen receptor-alpha (ESR1) gene

ABSTRACT: In this study we show that depletion of the cohesin subunit SMC3 or the Mediator subunit MED12 significantly impairs the ERα-regulated transcriptome. Surprisingly, SMC3 depletion appears to elicit this effect indirectly by rapidly decreasing ESR1 transcription and ERα protein levels. Moreover, we provide evidence that both SMC3 and MED12 colocalize on the ESR1 gene and are mutually required for occupancy as well as for transcriptional elongation. Finally, we show that extended proteasome inhibition decreases the mRNA expression of cohesin subunits which accompanies a decrease in ESR1 mRNA and ERα protein levels as well as estrogen-regulated transcription. Conclusions: These results identify the ESR1 gene as a cohesin/Mediator-dependent gene and indicate that this regulation may potentially be exploited for the treatment of estrogen-dependent breast cancer. This set contains 18 microarray samples with triplicates for each condition. 3 control siRNA, 3 control estrogen stimulated, 3 siRNA Med12 knockdown, 3 siRNA Med12 knockdown estrogen stimulated, 3 siRNA Smc3 knockdown, 3 siRNA Smc3 knockdown estrogen stimulated.

ORGANISM(S): Homo sapiens

SUBMITTER: Frank Kramer

PROVIDER: E-GEOD-38252 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Cohesin is required for expression of the estrogen receptor-alpha (ESR1) gene

Project description:In this study we show that depletion of the cohesin subunit SMC3 or the Mediator subunit MED12 significantly impairs the ERα-regulated transcriptome. Surprisingly, SMC3 depletion appears to elicit this effect indirectly by rapidly decreasing ESR1 transcription and ERα protein levels. Moreover, we provide evidence that both SMC3 and MED12 colocalize on the ESR1 gene and are mutually required for occupancy as well as for transcriptional elongation. Finally, we show that extended proteasome inhibition decreases the mRNA expression of cohesin subunits which accompanies a decrease in ESR1 mRNA and ERα protein levels as well as estrogen-regulated transcription. Conclusions: These results identify the ESR1 gene as a cohesin/Mediator-dependent gene and indicate that this regulation may potentially be exploited for the treatment of estrogen-dependent breast cancer.

2013-05-20 | GSE38252 | GEO

MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma [RNA-seq]

Project description:Uterine leiomyoma (LM) is the most common tumor in women. Estrogen and progesterone, via their receptors ERα and PR, play essential roles in LM growth. Mediator complex subunit 12 (MED12) mutations occur in 70% of all LM and are thought to drive tumor growth in a steroid hormone-dependent manner; however, the mechanisms remain unclear. Here, we performed ChIP-seq (ERα, PR, and MED12) and RNA-seq on LM expressing mutant MED12 (mut-MED12) or wild-type MED12 and matched myometrium. Mut-MED12 altered PR and chromatin interaction landscapes, with significant PR-binding site loss in proximal promoter regions in mut-MED12 LM. Integration of cistrome and transcriptome data identified tryptophan 2,3-dioxygenase (TDO2) as a PR and MED12 target gene, which was aberrantly upregulated in mut-MED12 LM. Kynurenine, the catabolic product of TDO2, was significantly elevated in mut-MED12 LM. Tryptophan or kynurenine treatment of primary LM cells activated the aryl hydrocarbon receptor (AHR) pathway, increased cell proliferation, and inhibited apoptosis; blocking the TDO2-kynurenine-AHR pathway by siRNA knockdown or pharmacologic inhibition abolished these effects. Mut-MED12 LM cells showed higher sensitivity to these treatments. These findings suggest that activation of the TDO2-kynurenine-AHR pathway in mut-MED12 LM induces tumor growth, and may inform the development of targeted treatments and precision medicine in LM.

2023-05-01 | GSE204969 | GEO

MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas

2023-05-01 | GSE204968 | GEO

The Chromatin-Looping Factor ZNF143 Engages at Looping Promoters to Favor the Estrogen Response in Breast Cancer (ChIP-seq)

Project description:Estrogen signaling in breast cancer cells relies on long-range chromatin interactions connecting distal regulatory elements bound by the estrogen receptor 1 (ESR1) to target gene promoters. This ensures stimulus and subtype-specific transcriptional responses. Expanding on the function of CTCF and the cohesin complex in breast cancer, we demonstrate that the chromatin-looping factor ZNF143 binds the promoter of most early-response estrogen target genes connected to distal regulatory elements in ESR1-positive breast cancer cells. Its chromatin occupancy is unaffected by estrogen stimulation, supporting a stable three-dimensional genomic architecture within the early response to estrogen. Its loss abrogates the estrogen-induced transcriptional response and growth of breast cancer cells. When taking into account CTCF, ZNF143 and cohesin complex subunits, we show that chromatin-looping factors are genetically altered in over 20% of ESR1-positive primary breast tumors. Furthermore, the overexpression of ZNF143, CTCF and RAD21, a cohesin complex subunit, in ESR1-positive breast tumors associates with a worse clinical outcome. Overall, our results suggest that ZNF143 is a new critical effector of the estrogen response and highlights the contribution of the chromatin looping machinery to ESR1-positive breast cancer development. Examination of genome-wide ZNF143 binding in MCF-7 cells

2016-08-09 | E-GEOD-76454 | biostudies-arrayexpress

The Chromatin-Looping Factor ZNF143 Engages at Looping Promoters to Favor the Estrogen Response in Breast Cancer (RNA-seq)

Project description:Estrogen signaling in breast cancer cells relies on long-range chromatin interactions connecting distal regulatory elements bound by the estrogen receptor 1 (ESR1) to target gene promoters. This ensures stimulus and subtype-specific transcriptional responses. Expanding on the function of CTCF and the cohesin complex in breast cancer, we demonstrate that the chromatin-looping factor ZNF143 binds the promoter of most early-response estrogen target genes connected to distal regulatory elements in ESR1-positive breast cancer cells. Its chromatin occupancy is unaffected by estrogen stimulation, supporting a stable three-dimensional genomic architecture within the early response to estrogen. Its loss abrogates the estrogen-induced transcriptional response and growth of breast cancer cells. When taking into account CTCF, ZNF143 and cohesin complex subunits, we show that chromatin-looping factors are genetically altered in over 20% of ESR1-positive primary breast tumors. Furthermore, the overexpression of ZNF143, CTCF and RAD21, a cohesin complex subunit, in ESR1-positive breast tumors associates with a worse clinical outcome. Overall, our results suggest that ZNF143 is a new critical effector of the estrogen response and highlights the contribution of the chromatin looping machinery to ESR1-positive breast cancer development. mRNA profiles of MCF-7 cells (siCtl or siZNF143) under vehicle (EtOH) or E2 (10 uM 17-beta oestradiol) stimulation

2016-08-09 | E-GEOD-76453 | biostudies-arrayexpress

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.

2013-09-01 | GSE47803 | GEO

Targeting kinome reprogramming in ESR1 fusion-driven metastatic breast cancer

Project description:Transcriptionally active ESR1 fusions promote endocrine therapy (ET)-resistant growth and metastasis of estrogen receptor-alpha positive (ERα+) breast cancer. Currently, there are no targeted treatment options for tumors harboring active fusions because the ESR1 ligand binding domain (LBD) has been replaced with non-drug binding sequences from the 3’ partner gene. A mass spectrometry (MS)-based Kinase Inhibitor Pulldown Assay (KIPA) demonstrated an increase of multiple receptor tyrosine kinases including RET in T47D cells expressing active ESR1 fusions. Integrated proteogenomics defined tumor subsets that could be responsive to RET and CDK4/6 directed therapy from 22 biologically heterogeneous ERα+ patient-derived xenograft (PDX) tumors. Inhibition of RET by repurposing an FDA-approved drug significantly suppressed ESR1 fusion-driven growth of cell, PDX-derived organoid (PDXO) and PDX models. CDK4/6 inhibitor treatment showed similar tumor reductions to RET inhibition. Here, we reveal therapeutic kinase vulnerabilities in ESR1 fusion-driven tumors, which will lay the framework for future clinical trials.

2023-10-24 | PXD033339 | Pride

Architectural protein subclasses shape 3-D organization of genomes during lineage commitment

Project description:Understanding the topological configurations of chromatin can reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3-D interactions that undergo marked reorganization at the sub-Mb scale during differentiation. Distinct combinations of CTCF, Mediator, and cohesin show widespread enrichment in architecture at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant sub-domains. Conversely, Mediator/cohesin together with pioneer factors bridge short-range enhancer-promoter interactions within and between larger sub-domains. Knockdown of Smc1 or Med12 in ES cells results in disruption of spatial architecture and down-regulation of genes found in cohesin-mediated interactions. We conclude that cell type-specific chromatin organization occurs at the sub-Mb scale and that architectural proteins shape the genome in hierarchical length scales. Analysis of higher-order chromatin chromatin architecture in mouse ES cells and ES-derived NPCs. Analysis of CTCF and Smc1 occupied sites in ES-derived NPCs.

2013-05-24 | E-GEOD-36203 | biostudies-arrayexpress

Whole-genome DNA methylation profiling of ESR1 Q375H and R394H mutations from the human breast cancer MB-231 stable cells.

Project description:Estrogen insensitivity syndrome (EIS) arises from rare mutations in estrogen receptor α (ERα, encoded by ESR1 gene) resulting in the inability of estrogen to exert its biological effects. Due to the rarity, mutations in ESR1 gene and the underlying molecular mechanisms of EIS have not been thoroughly studied. We used human EPIC DNA methylation array to comparison of the transcriptome between the WT ESR1 and Q375H and R394H clinical mutants in MB231 stable cell lines.

2020-10-22 | GSE139687 | GEO

Expression data from MCF7 cells depleted of the cohesin subunit RAD21 and treated with estrogen or vehicle

Project description:RAD21 is a subunit of cohesin. Cohesin is maninly known for its role in holding sister chromatids together during cell-division but it also plays a role in gene regulation. Genome wide study in MCF7 cells have shown that cohesin co-binds with estrogen receptor alpha at numerous sites. To identify estrogen sensitive genes that are influenced by cohesin, a microarray expression analysis was conducted in MCF7 cells lacking the cohesin subunit RAD21. Global changes in gene expression were identified in cells treated with Control/RAD21 siRNA and stimulated with estrogen/vehicle thereafter.

2016-01-30 | GSE59908 | GEO

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