Language

English

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

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.

Keywords

Animals, Female, Humans, Mice, Endometriosis, Endometrium, Estrogens, Neoplasm Proteins, Progesterone, Receptors, Progesterone, Receptors, Steroid, Steroids

Published Open-Access

yes

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