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Genome-wide estrogen receptor-α binding and action in human endometrial stromal cells [ChIP-Seq]

ABSTRACT: Endometrial estrogen receptor-α (ESR1) is indispensable for epithelial and stromal proliferation and differentiation during decidualization, yet the gene targets of estradiol (E2) / ESR1 in human stromal cells and associated mechanisms remain unknown. In this study, we characterized global E2-ESR1‒dependent transcriptomic changes and ESR1 recruitment to chromatin. Human endometrial stromal cells were isolated from 4 premenopausal women for primary cell culture. Genome-wide RNA expression by RNA-sequencing was compared in endometrial stromal cells with or without siRNA knockdown of ESR1 in the presence or absence of E2 (n=2). Genome-wide recruitment of ESR1 to chromatin was assessed by chromatin immunoprecipitation sequencing using an antibody against ESR1 was performed to examine binding to target genes (n=1).

ORGANISM(S): Homo sapiens

PROVIDER: GSE151393 | GEO | 2020/07/06

REPOSITORIES: GEO

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Project description:Ovarian estrogen (E2) and progesterone (P4) are indispensable for embryo-implantation and endometrial stromal decidualization; however, the molecular mechanisms that underpin these reproductive processes are unclear. Steroid receptor coregulator-2 (SRC-2) belongs to the multifunctional SRC/p160 family which also includes SRC-1 and SRC-3. Sharing strong sequence homology, all three SRCs exert diverse regulatory effects by modulating the transcriptional potency of nuclear receptor family members, including the estrogen and progesterone receptor (ER and PR respectively). Importantly, absence of SRC-2 in PR positive cells in the epithelial, stromal, and myometrial compartments of the murine uterus results in a striking infertility defect. This reproductive phenotype highlights a key role for SRC-2 in uterine function which is not shared with other coregulators. Intriguingly, abrogation of uterine SRC-2 does not block embryo apposition or attachment to the apical surface of luminal epithelial cells of the endometrium but rather prevents P4-dependent local decidualization of the sub-epithelial stroma. Remarkably, epithelial-specific ablation of SRC-2 in the murine uterus does not compromise endometrial functionality, again underscoring the unique importance of stromal derived SRC-2 in uterine function. The stromal decidualization defect resulting from SRC-2 ablation is reflected at the molecular level by a marked attenuation in P4 responsive target genes known to be critical for P4 dependent decidualization (i.e. ERBB receptor feedback inhibitor 1, Follistatin and Fkbp5). Conversely, the induction of E2 or P4 target genes involved in embryo implantation (i.e. leukemia inhibitory factor (LIF) and Indian hedgehog (Ihh) respectively) is not affected by SRC-2’s absence. As with mouse studies, decidualization of primary human stromal cells (HESCs) in culture is blocked by SRC-2 knockdown; however, HESC decidualization is unaffected by knockdown of SRC-1 or SRC-3. As a consequence of SRC-2 knockdown, molecular studies disclose a striking decrease in the induction of a subset of P4 target genes (i.e. WNT4 and FKBP5) which are essential for the stromal-epithelioid transformation step, the cellular hallmark of endometrial decidualization. Collectively, these studies not only showcase the evolutionary importance of SRC-2 in endometrial biology but also suggest that deregulation of this coregulator may underpin a spectrum of hormone-dependent uterine pathologies such as endometriosis and endometrial cancer.

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Genome-wide estrogen receptor-α binding and action in human endometrial stromal cells [ChIP-Seq]

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