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 and Ramakrishna Kommagani ()
Additional contact information
Sangappa B. Chadchan: Baylor College of Medicine, One Baylor Plaza
Pooja Popli: Baylor College of Medicine, One Baylor Plaza
Zian Liao: Baylor College of Medicine, One Baylor Plaza
Eryk Andreas: Washington University School of Medicine
Michelle Dias: Baylor College of Medicine, One Baylor Plaza
Tianyuan Wang: Integrative Bioinformatics, National Institute of Environmental Health Sciences
Stephanie J. Gunderson: Washington University School of Medicine
Patricia T. Jimenez: Washington University School of Medicine
Denise G. Lanza: Baylor College of Medicine, One Baylor Plaza
Rainer B. Lanz: Baylor College of Medicine, One Baylor Plaza
Charles E. Foulds: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza
Diana Monsivais: Baylor College of Medicine, One Baylor Plaza
Francesco J. DeMayo: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences
Hari Krishna Yalamanchili: Baylor College of Medicine, One Baylor Plaza
Emily S. Jungheim: Washington University School of Medicine
Jason D. Heaney: Baylor College of Medicine, One Baylor Plaza
John P. Lydon: Baylor College of Medicine, One Baylor Plaza
Kelle H. Moley: Washington University School of Medicine
Bert W. O’Malley: Baylor College of Medicine, One Baylor Plaza
Ramakrishna Kommagani: Baylor College of Medicine, One Baylor Plaza

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46180-4

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