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

초록

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. Cfp1(f/f);Pgr-Cre (Cfp1(d/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, Cfp1(d/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. Progesterone (P-4) signalling is involved in physiological control of the endometrium and contributes to the pathogenesis of endometrial diseases such as endometriosis. Here the authors report that CFP1, a regulator of histone methylation, controls endometrial responses to P-4 and lack of endometrial CFP1 leads to failure of embryo implantation and exacerbated experimental endometriosis in mice.

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