CFP1 Governs Uterine Epigenetic Landscapes To Intervene in Progesterone Responses for Uterine Physiology and Suppression of Endometriosis

Authors

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
Haengseok Song

Publication Date

6-3-2023

Journal

Nature Communications

DOI

10.1038/s41467-023-39008-0

PMID

37270588

PMCID

PMC10239508

PubMedCentral® Posted Date

6-3-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Female, Humans, Mice, Pregnancy, Embryo Implantation, Endometriosis, Endometrium, Epigenesis, Genetic, Progesterone, Receptors, Progesterone, RNA, Messenger, Uterus, Trans-Activators, Infertility, Embryology, Epigenetics

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.

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