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

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.