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 , Haengseok Song
Nat Commun. 2023 Jun 3;14(1):3220. doi: 10.1038/s41467-023-39008-0.
[Abstract]
Progesterone (P
4) is required for the preparation of the endometrium for a successful pregnancy. P
4 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 P
4-progesterone receptor (PGR) signaling networks in the mouse uterus.
Cfp1f/f;
Pgr-Cre (
Cfp1d/d) mice showed impaired P
4 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 P
4 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 P
4 resistance, which was rescued by a smoothened agonist. In human endometriosis, CFP1 was significantly downregulated, and expression levels between CFP1 and these P
4 targets are positively related regardless of PGR levels. In brief, our study provides that CFP1 intervenes in the P
4-epigenome-transcriptome networks for uterine receptivity for embryo implantation and the pathogenesis of endometriosis.
- Fulltext : https://www.nature.com/articles/s41467-023-39008-0