CFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis

Seung Chel Yang, Mira Park, Kwon-Ho Hong, Hyeonwoo La, Chanhyeok Park, Peike Wang, Gaizhen Li, Qionghua Chen, Youngsok Choi, Francesco J. DeMayo, John P. Lydon, David G. Skalnik, Hyunjung J. Lim, Seok-Ho Hong, So Hee Park, Yeon Sun Kim, Hye-Ryun Kim and Haengseok Song ()
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Seung Chel Yang: CHA University
Mira Park: CHA University
Kwon-Ho Hong: Konkuk University
Hyeonwoo La: Konkuk University
Chanhyeok Park: Konkuk University
Peike Wang: The First Affiliated Hospital of Xiamen, School of Medicine, Xiamen University, Xiamen
Gaizhen Li: The First Affiliated Hospital of Xiamen, School of Medicine, Xiamen University, Xiamen
Qionghua Chen: The First Affiliated Hospital of Xiamen, School of Medicine, Xiamen University, Xiamen
Youngsok Choi: Konkuk University
Francesco J. DeMayo: National Institute of Environmental Health Sciences
John P. Lydon: Baylor College of Medicine
David G. Skalnik: Indiana University-Purdue University Indianapolis
Hyunjung J. Lim: Konkuk University
Seok-Ho Hong: Kangwon National University
So Hee Park: CHA University
Yeon Sun Kim: CHA University
Hye-Ryun Kim: CHA University
Haengseok Song: CHA University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent but also in H3K4me3-independent manners. CFP1 directly regulates important P4 response genes, including Gata2, Sox17, and Ihh, which activate smoothened signaling pathway in the uterus. In a mouse model of endometriosis, Cfp1d/d ectopic lesions showed P4 resistance, which was rescued by a smoothened agonist. In human endometriosis, CFP1 was significantly downregulated, and expression levels between CFP1 and these P4 targets are positively related regardless of PGR levels. In brief, our study provides that CFP1 intervenes in the P4-epigenome-transcriptome networks for uterine receptivity for embryo implantation and the pathogenesis of endometriosis.

Date: 2023
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DOI: 10.1038/s41467-023-39008-0

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