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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139397 | GEO | 2022/03/09

REPOSITORIES: GEO

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Project description:Although non-genomic steroid receptor pathways have been studied over the past decade, little is known about the direct gene expression changes that take place as a consequence of their activation. Progesterone controls proliferation of rat endometrial stromal cells during the peri-implantation phase of pregnancy. We showed that picomolar concentration of progestin R5020 mimics this control in UIII endometrial stromal cells via ERK1-2 and AKT activation mediated by interaction of Progesterone Receptor (PR) with Estrogen Receptor beta (ERb) and without transcriptional activity of endogenous PR and ER. Here we identify early downstream targets of cytoplasmic PR signaling and their possible role in endometrial stromal cell proliferation. Microarray analysis of global gene expression changes in UIII cells treated for 45 min with progestin identified 97 up- and 341 down-regulated genes. The most over-represented molecular functions were transcription factors and regulatory factors associated with cell proliferation and cell cycle, a large fraction of which were repressors down-regulated by hormone. Further analysis verified that progestins regulate Ccnd1, JunD, Usf1, Gfi1, Cyr61, and Cdkn1b through PR-mediated activation of ligand-free ER, ERK1-2 or AKT, in the absence of genomic PR binding. ChIP experiments show that progestin promoted the interaction of USF1 with the proximal promoter of the Cdc2 gene, and Usf1 knockdown abrogated Cdc2 progestin-dependent transcriptional regulation providing a mechanism for direct regulation of its expression. Finally, Cdc2 knockdown blocked R5020 induced UIII cell proliferation. We conclude that progestin induced proliferation of endometrial stromal cells requires ERK1-2 and AKT mediated early regulation of USF1, that induces Cdc2. To our knowledge, this is the first description of early target genes of progestin-activated classical PR via crosstalk with protein kinases and independently of hormone receptor binding to the genomic targets.