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:Endometriosis is associated with aberrant gene expression in the eutopic endometrium of women with disease. To determine if the development of endometriotic lesions directly impacts eutopic endometrial gene expression, we sequentially analyzed the eutopic endometrium across the time course of disease progression in a baboon model of induced disease. Endometriosis was induced in baboons by intraperitoneal inoculation of autologous menstrual endometrium. Eutopic endometria were collected at 9-11 days postovulation) in five time points: 1, 3, 6-7, 10-12, and 15-16 months after disease induction and compared with tissue from disease-free baboons. We used microarrays to identify differentially expressed genes between time points. Sequential analysis of the same animals during disease progression demonstrated an early disease insult and a transitory dominance of an estrogenic phenotype. However, as the disease progressed, a progesterone-resistant phenotype became evident. Endometriosis was experimentally induced in Papio anubis female baboons (n = 4) by intraperitoneal inoculation with menstrual endometrium on two consecutive menstrual cycles. Baboons with spontaneous endometriosis (n = 2) were also included in this study with an unknown duration of disease. Control endometrium was similarly harvested from animals (n = 4) with no previous surgeries and with no visible disease. The progression of disease was monitored in each animal by consecutive laparoscopies and video recording at 1 (n = 2), 3 (n = 4), 6-7 (n = 4), 10-12, (n = 4), and 15-16 (n = 3) months after inoculation during a window of 9-11 days postovulation. Eutopic endometrial tissues were harvested and were snap frozen in liquid nitrogen for RNA extraction. Additionally, menstrual endometrium was harvested on Days 1-2 of menses using a Unimar Pipelle (Cooper Surgical Inc., Shelton, CT) immediately prior to laparoscopy. Blood samples were collected daily from days 7 through 16 postmenstruation of menstrual cycles.

Project description:Eutopic endometrium in endometriosis has molecular evidence of resistance to progesterone (P4) and activation of the PKA pathway in the stromal compartment. To investigate global and temporal responses of eutopic endometrium to P4, we compared early (6-h), intermediate (48-h), and late (14-day) transcriptomes, signaling pathways, and networks of human endometrial stromal fibroblasts (hESFs) from women with endometriosis (hESFendo) to hESFs from women without endometriosis (hESFnonendo). Endometrial biopsy samples were obtained from subjects with and without mild peritoneal endometriosis (n = 4 per group), and hESFs were isolated and treated with P4 (1 μM) plus estradiol (E2) (10 nM), E2 alone (10 nM), or vehicle for up to 14 days. Total RNA was subjected to microarray analysis using a Gene 1.0 ST (Affymetrix) platform and analyzed by using bioinformatic algorithms, and data were validated by quantitative real-time PCR and ELISA. Results revealed unique kinetic expression of specific genes and unique pathways, distinct biological and molecular processes, and signaling pathways and networks during the early, intermediate, and late responses to P4 in both hESFnonendo and hESFendo, although a blunted response to P4 was observed in the latter. The normal response of hESF to P4 involves a tightly regulated kinetic cascade involving key components in the P4 receptor and MAPK signaling pathways that results in inhibition of E2-mediated proliferation and eventual differentiation to the decidual phenotype, but this was not established in the hESFendo early response to P4. The abnormal response of this cell type to P4 may contribute to compromised embryonic implantation and infertility in women with endometriosis. We compared early (6-h), intermediate (48-h), and late (14-day) in vitro whole-genome responses of hESF from women with endometriosis (hESFendo) to hESF from women without endometriosis (hESFnonendo) treated with P4 plus E2 (E2P4), E2 alone, or vehicle alone. Using this experimental paradigm, the data demonstrate unique phenotypes, gene expression processes, biochemical and signaling pathways, and networks suggestive of early, intermediate, and late responses of hESFnonendo and hESFendo to P4, giving insights into the complexity of events occurring normally in response to P4 and in the setting of endometriosis.

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Krüppel-like Factor 9 and Progesterone Receptor Co-Regulation of Decidualizing Endometrial Stromal Cells: Implications for its Loss in the Pathogenesis of Endometriosis

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