Project description:Progesterone (P4) is essential to prepare the endometrium for a successful pregnancy. While P4 resistance is a major cause of infertility that leads to endometrial disorders, such as endometriosis, the underlying epigenetic imbalance responsible for P4 resistance in the endometrium remains unclear. We demonstrated that CXXC finger protein 1 (CFP1), a major mediator of histone H3 lysine 4 trimethylation (H3K4m3), is an indispensable factor in the maintenance of epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the uterus. Cfp1flox/flox;Pgr-Cre (Cfp1d/d) mice suffered from impaired P4 responses, leading to abnormal uterine cell proliferation and complete failure of embryo implantation and decidualization, albeit regular estrous cycle with normal hormone profiles. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 binding enriches promoter regions to regulate uterine mRNA landscapes not only in H3K4me3-dependent but also in H3K4me3-independent manners. Especially, CFP1 directly regulates subsets of important P4 response genes, including Gata2, Sox17, and Ihh, which mediate the activation of the smoothened signaling pathway in the uterus. P4 cannot interfere with E2 actions on uterine epithelial proliferation in Cfp1d/d mice, which was restored by supplementing a smoothened agonist (SAG). Furthermore, ectopic lesions of Cfp1d/d uterus in an endometriosis model showed P4 resistance, which was rescued by SAG. In human endometriosis, CFP1, GATA2, SOX17, and IHH, were significantly downregulated, and a positive correlation was found in the expression levels between CFP1 and these P4 targets regardless of PGR levels. Collectively, we suggest that CFP1 is an epigenetic modulator of P4-PGR signaling networks to promote uterine receptivity for embryo implantation and suppress endometriosis with P4 resistance. CFP1 is a key epigenetic factor that intervenes in the P4–epigenome–transcriptome networks for uterine function under physiologic and pathophysiologic conditions.

Project description:The present investigation examined the spatiotemporal expression of estrogen receptors (ER-alpha and ER-beta) and progesterone receptor (PR) in the periimplantation mouse uterus (days 1-8). ER-alpha messenger RNA (mRNA) was detected at much higher levels in the periimplantation uterus compared with that of ER-beta mRNA, the levels of which were very low in all uterine cells during this period. Results of in situ hybridization demonstrated expression of ER-alpha mRNA primarily in the luminal and glandular epithelia on days 1 and 2 of pregnancy. On days 3 and 4, the accumulation was localized primarily in stromal cells in addition to its presence in the epithelium. Following implantation on day 5, the accumulation of this mRNA was more condensed in the luminal and glandular epithelia, but declined in the subluminal epithelial stroma at the sites of implanting embryos. On days 6-8, the accumulation of ER-alpha mRNA was primarily localized in the secondary decidual zone (SDZ) with more intense localization in the subepithelial cells at the mesometrial pole. In contrast, signals were very low to undetectable in the primary decidual zone (PDZ), and no signals were detected in implanting embryos. The undifferentiated stroma underneath the myometrium also showed positive signals. The immunolocalization of ER-alpha protein correlated with the mRNA localization. Western blot analysis showed down-regulation of ER-alpha in day 8 decidual cell extracts consistent with the down-regulation of ER-alpha mRNA in decidual cells immediately surrounding the embryo on this day. The expression pattern of PR was also dynamic in the periimplantation uterus. On day 1, the accumulation of PR mRNA was very low to undetectable, whereas only a modest level of accumulation in the epithelium was noted on day 2. On days 3 and 4, the accumulation of this mRNA was detected in both the epithelium and stroma. In contrast, the expression was restricted only to the stroma with increased signals at the sites of implantation on day 5. On days 6-8, PR mRNA accumulation increased dramatically throughout the deciduum. The localization of immunoreactive PR correlated with the mRNA distribution in the periimplantation uterus. Taken together, the results demonstrate that the expression of ER-alpha, ER-beta, and PR is differentially regulated in the periimplantation mouse uterus. This compartmentalized expression of ER and PR provides information regarding the sites of coordinated effects ofestrogen and progesterone in the preparation of the uterus for implantation and decidualization during early pregnancy.

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Progesterone Alleviates Endometriosis via Inhibition of Uterine Cell Proliferation, Inflammation and Angiogenesis in an Immunocompetent Mouse Model.

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