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Nucleosome driven transcription factor binding and gene regulation [microarray]

ABSTRACT: Elucidating the global function of a transcription factor implies the identification of its target genes and genomic binding sites. The role of chromatin in this context is unclear, but the dominant view is that factors bind preferentially to nucleosome-depleted regions, identified as DNaseI-hypersensitive sites (DHS). Here we show by chromatin-IP, MNase and DNaseI assays followed by deep sequencing that the progesterone receptor (PR) requires nucleosomes for optimal binding and function. In breast cancer cells treated with progestins we identified 25,000 PR binding sites (PRbs), the majority encompassing several copies of the hexanucleotide TGTYCY, highly abundant in the genome. We found that functional PRbs accumulate around progesterone-induced genes mainly in enhancers, are enriched in DHS but exhibit high nucleosome occupancy. Progestin stimulation results in remodeling of these nucleosomes with displacement of histones H1 and H2A/H2B dimers. Our results strongly suggest that nucleosomes are crucial for PR binding and hormonal gene regulation. Keywords: time course

ORGANISM(S): Homo sapiens

PROVIDER: GSE41502 | GEO | 2012/12/01

SECONDARY ACCESSION(S): PRJNA177704

REPOSITORIES: GEO

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Nucleosome driven transcription factor binding and gene regulation [microarray]

Project description:Elucidating the global function of a transcription factor implies the identification of its target genes and genomic binding sites. The role of chromatin in this context is unclear, but the dominant view is that factors bind preferentially to nucleosome-depleted regions, identified as DNaseI-hypersensitive sites (DHS). Here we show by chromatin-IP, MNase and DNaseI assays followed by deep sequencing that the progesterone receptor (PR) requires nucleosomes for optimal binding and function. In breast cancer cells treated with progestins we identified 25,000 PR binding sites (PRbs), the majority encompassing several copies of the hexanucleotide TGTYCY, highly abundant in the genome. We found that functional PRbs accumulate around progesterone-induced genes mainly in enhancers, are enriched in DHS but exhibit high nucleosome occupancy. Progestin stimulation results in remodeling of these nucleosomes with displacement of histones H1 and H2A/H2B dimers. Our results strongly suggest that nucleosomes are crucial for PR binding and hormonal gene regulation. Keywords: time course Whole genome expression microarrays were performed in T47D-MTVL cells stimulated 0, 1 and 6 hr with 10 nM of progestin R5020. 3 biological replicas were performed for T0 and 6 hr treatments and 4 for the one of 1hr.

2012-12-01 | E-GEOD-41502 | biostudies-arrayexpress

Nucleosome driven transcription factor binding and gene regulation [ChIP-Seq]

2012-12-01 | GSE41466 | GEO

Nucleosome driven transcription factor binding and gene regulation [ChIP-Seq]

Project description:Elucidating the global function of a transcription factor implies the identification of its target genes and genomic binding sites. The role of chromatin in this context is unclear, but the dominant view is that factors bind preferentially to nucleosome-depleted regions, identified as DNaseI-hypersensitive sites (DHS). Here we show by chromatin-IP, MNase and DNaseI assays followed by deep sequencing that the progesterone receptor (PR) requires nucleosomes for optimal binding and function. In breast cancer cells treated with progestins we identified 25,000 PR binding sites (PRbs), the majority encompassing several copies of the hexanucleotide TGTYCY, highly abundant in the genome. We found that functional PRbs accumulate around progesterone-induced genes mainly in enhancers, are enriched in DHS but exhibit high nucleosome occupancy. Progestin stimulation results in remodeling of these nucleosomes with displacement of histones H1 and H2A/H2B dimers. Our results strongly suggest that nucleosomes are crucial for PR binding and hormonal gene regulation. T47D-MTVL human breast cancer cells were incubated with the progestin R5020 for different times between 0 to 360 minutes at 37ÂºC. ChIP-seq experiments were performed using antibodies against progesterone receptor and a single Sample each with anti-H3K4me3 and anti-H3K4me1. Mononucleosomal DNA was prepared from cells untreated or stimulated 60 min with R5020 and subjected to deep sequencing using the Solexa Genome Analyzer.

2012-12-01 | E-GEOD-41466 | biostudies-arrayexpress

A small set of accessible enhancers enables breast cancer cell response to physiological progestin concentrations

Project description:Here, we report that in T47D breast cancer cells 50pM progestin is sufficient to activate cell cycle entry and the progesterone gene expression program in breast cancer cells. At this concentration, equivalent to the progesterone blood levels found around the menopause, PR binds only to 2,800 genomic sites, which are accessible to ATAC cleavage prior to hormone. These Highly-Accessible PR Binding sites (HAPRBs) are surrounded by well-organized nucleosomes and exhibit breast enhancer features, including higher estrogen receptor (ERa), FOXA1 and BRD4 occupancy. Although, HAPRBs are enriched in RAD21 and CTCF, PR binding is the driving force for the most robust interactions with hormone-regulated genes. HAPRBs show higher frequency of 3D contacts among themselves than with other PRBs, indicating co-localization in similar compartment. Gene regulation via HAPRBs is independent of classical co-regulators and ATP-activated remodelers, relaying mainly on MAP kinase activation that enables PR nuclear engagement. HAPRBs are also preferentially occupied by PR and ERa in breast cancer xenografts derived from MCF-7 cells as well as from patients (PDXs), indicating their usefulness as potential targets for therapeutic intervention.

2021-12-06 | GSE179666 | GEO

Higher-order chromatin organization defines PR and PAX2 binding to regulate endometrial cancer cell gene expression (Hi-C)

Project description:Estrogen (E2) and Progesterone (Pg) via their specific receptors, ER and PR respectively, are major determinants in the development and progression of endometrial malignancies. We have studied how E2 and the synthetic progestin R5020 affect genomic function in Ishikawa endometrial cancer cells. Using ChIPseq in cells exposed to the corresponding hormones, we identified cell specific binding sites for ER (ERbs) and PR (PRbs), mostly binding to independent sites and both adjacent to PAXbs. Long-range interactions (HiC) showed enrichment of PRbs and PAXbs, which we call progestin control regions (PgCRs) inside TADs with differentially progestin-regulated genes. Effects of hormone treatments on gene expression were detected by RNAseq. PgCRs correlate with open chromatin independently of hormonal stimuli. In summary, endometrial response to progestins in differentiated endometrial tumor cells results in part from binding of PR to compartmentalized PgCRs in hormone-independent open chromatin, which include binding of partner transcription factors, in particular PAX2.

2022-03-09 | GSE139397 | GEO

Higher-order chromatin organization defines PR and PAX2 binding to regulate endometrial cancer cell gene expression (ChIPseq PAX2)

2022-03-09 | GSE139395 | GEO

Higher-order chromatin organization defines PR and PAX2 binding to regulate endometrial cancer cell gene expression (ChIPseq)

2022-03-09 | GSE139394 | GEO

Higher-order chromatin organization defines PR and PAX2 binding to regulate endometrial cancer cell gene expression (ATACseq)

2022-03-09 | GSE139396 | GEO

Higher-order chromatin organization defines PR and PAX2 binding to regulate endometrial cancer cell gene expression (RNAseq)

2022-03-09 | GSE139393 | GEO

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer. [ChIP-seq]

Project description:Transcriptomic changes and estrogen and progesterone receptor binding in multiple ER+/PR+ models (eight ER+/PR+ patient tumors, various T47Ds, ZR75) and multiple ER+/PR-negative models (four ER+/PR- patient tuumors, PR-deficient T47D and MCF7 cells) treated with various hormone combinations. Results: In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. Importantly, when both hormones are present, progestin modulates estrogen action such that responsive transcriptomes, cellular processes and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Conclusions: Genomic Agonism and Phenotypic Antagonism between Estrogen and Progesterone Receptors in Breast Cancer. Individual and concerted actions of ER and PR highlight the prognostic and therapeutic value of PR in ER+/PR+ breast cancers.

2016-06-01 | GSE80367 | GEO

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