Nature Communications (Mar 2024)

A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis

  • Sangappa B. Chadchan,
  • Pooja Popli,
  • Zian Liao,
  • Eryk Andreas,
  • Michelle Dias,
  • Tianyuan Wang,
  • Stephanie J. Gunderson,
  • Patricia T. Jimenez,
  • Denise G. Lanza,
  • Rainer B. Lanz,
  • Charles E. Foulds,
  • Diana Monsivais,
  • Francesco J. DeMayo,
  • Hari Krishna Yalamanchili,
  • Emily S. Jungheim,
  • Jason D. Heaney,
  • John P. Lydon,
  • Kelle H. Moley,
  • Bert W. O’Malley,
  • Ramakrishna Kommagani

DOI
https://doi.org/10.1038/s41467-024-46180-4
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 17

Abstract

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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.