Publication Date
3-2-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-46180-4
PMID
38431630
PMCID
PMC10908778
PubMedCentral® Posted Date
3-2-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Female, Humans, Mice, Endometriosis, Endometrium, Estrogens, Neoplasm Proteins, Progesterone, Receptors, Progesterone, Receptors, Steroid, Steroids
Abstract
Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions.
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Diseases Commons, Medical Sciences Commons, Mental and Social Health Commons, Obstetrics and Gynecology Commons, Women's Health Commons
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