Progesterone receptor in uterine glands is required for pregnancy establishment in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE292591 | GEO | 2025/03/26
REPOSITORIES: GEO
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Project description:Uterine receptivity (the window of implantation) is essential for successful implantation. The concept of uterine receptivity was first discovered 50 years ago by Psychoyos. In mice, uterine receptivity begins with the secretion of LIF from uterine glands stimulated by estrogen on the morning of day 4 pregnancies. However, some implantation failure is due to the lack of responses to the estrogen secretion. The current study reveals that uterine glands undergo a differentiation process with increases in more branches during the preimplantation period. The single cell RNA profiling of glandular cells identifies that LIF is expressed exclusively in a Prss29+ subgroup of glands in response to estrogen secretion on day 4 of pregnancy. Previous studies have shown that Foxa2 deficiency in uterine glands results in implantation failure due to lack of LIF production. Interestingly, Foxa2-deficient glands fail to develop branches and the functional Prss29+ subgroup of gland cells, indicating FOXA2 is obligatory for normal glandular differentiation prior to implantation. We found that this group develops by the evening of day 3 of pregnancy prior to estrogen secretion on day 4 mornings. We noticed that Lif mRNA signals are detected in the uterus comprising the Prss29+ subgroup. Our findings indicate that uterine glands undergo a FOXA2-dependent maturation process to acquire the competence, which we have termed the “transitional phase,” necessary to respond to estrogen. This newly identified glandular "transitional phase" represents a landmark concept in the study of uterine receptivity and implantation biology.
2025-02-15 | GSE275806 | GEO
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.
2023-05-10 | GSE219103 | GEO
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.
2023-05-10 | GSE219102 | GEO
Project description:In this study, whole transcriptome changes induced by P4 were analysed by RNAseq following laser capture microdissection (LCM) of endometrial biopsies to isolate LE, GE and ST cells. The study was performed in cows without any sign of uterine disease (as assessed by uterine cytology). At 45 days postpartum, the presence of a Corpus Luteum (CL) assessed by ultrasonography and plasma P4 concentrations were used to categorise healthy cows at 45 days postpartum determine if cows were in luteal phase (CL, P4 concentrations ≥1 ng/ml; n=4) or not (no CL, P4 concentrations < 1ng/ml; n=9). Overall, endometrial LE, GE, and ST cells shown specific transcriptomic profiles with different proportions and type of genes expressed over 10 tpm. Most of the genes differentially expressed (DEGs) in response to P4 were cell type-specific (93.9%). Genes involved in cell cycle and nuclear division were under-expressed in presence of P4 in GE and LE, highlighting the anti-proliferative action of P4 in epithelial cells. Elevated P4 concentrations were also associated with the under-expression of estrogen receptor 1 (ESR1) in GE and of oxytocin receptor (OXTR) in GE and ST. In ST, transcription factors such as SOX17 and FOXA2 , as well as interferon related genes which are known to regulate uterine epithelial–stromal crosstalk conveying to endometrial receptivity for embryo implantation, were over-expressed under P4. The results from this study show that progesterone regulates endometrial function in a cell type specific way, which looks independent of the expression of its main receptor PGR. These novel insights into uterine physiology, stand the cell compartment, rather than the whole tissue, as a physiological unit.
2021-12-03 | GSE182932 | GEO
Project description:RNA-seq analysis of uterine luminal epithelium at D4.5 indicates that epithelial PGRA and PGRB shares conseved pathways. Constitutive epithelial PGRA and PGRB disrupts the embryo implantation both through the suppressed FOXO1 signaling by excluding FOXO1 from the nuclear at the uterine epithelium. There are three layers of regulation. Firstly, PGRA and PGRB diminishes Lif transcription in uterine glands by blocking ESR1 binding at the Lif promoter at D3.5 which is critical for the FOXO1 nuclear expression at D4.5 through LIF/pSTAT3/FOXO1. Secondly, PGRA and PGRB directly suppres Foxo1 transcription at the uterine epithelium probably through direct binding at Foxo1 promoter. Thirdly, PGRA and PGRB promotes the Sgk1 transcription, the kinases that phosphorylate FOXO1 to translocate it into cytoplasma for degradation.
2021-12-02 | GSE178540 | GEO
Project description:RNA-seq analysis of uterine luminal epithelium at D4.5 indicates that epithelial PGRA and PGRB shares conseved pathways. Constitutive epithelial PGRA and PGRB disrupts the embryo implantation both through the suppressed FOXO1 signaling by excluding FOXO1 from the nuclear at the uterine epithelium. There are three layers of regulation. Firstly, PGRA and PGRB diminishes Lif transcription in uterine glands by blocking ESR1 binding at the Lif promoter at D3.5 which is critical for the FOXO1 nuclear expression at D4.5 through LIF/pSTAT3/FOXO1. Secondly, PGRA and PGRB directly suppres Foxo1 transcription at the uterine epithelium probably through direct binding at Foxo1 promoter. Thirdly, PGRA and PGRB promotes the Sgk1 transcription, the kinases that phosphorylate FOXO1 to translocate it into cytoplasma for degradation.
2021-12-02 | GSE178539 | GEO
Project description:RNA-seq analysis of uterine luminal epithelium at D4.5 indicates that epithelial PGRA and PGRB shares conseved pathways. Constitutive epithelial PGRA and PGRB disrupts the embryo implantation both through the suppressed FOXO1 signaling by excluding FOXO1 from the nuclear at the uterine epithelium. There are three layers of regulation. Firstly, PGRA and PGRB diminishes Lif transcription in uterine glands by blocking ESR1 binding at the Lif promoter at D3.5 which is critical for the FOXO1 nuclear expression at D4.5 through LIF/pSTAT3/FOXO1. Secondly, PGRA and PGRB directly suppres Foxo1 transcription at the uterine epithelium probably through direct binding at Foxo1 promoter. Thirdly, PGRA and PGRB promotes the Sgk1 transcription, the kinases that phosphorylate FOXO1 to translocate it into cytoplasma for degradation.
2021-12-02 | GSE178538 | GEO
Project description:Uterine glands are essential for pregnancy in mice and likely humans, because they secrete or transport bioactive substances that regulate uterine receptivity for blastocyst implantation. In mice, the uterus becomes receptive to blastocyst implantation on day 4, but is refractory by day 5. Here, blastocysts could be recovered from progesterone-induced uterine gland (PUGKO) but not wildtype (WT) mice on day 5 post-mating. Anti-adhesive Muc1 protein and microvilli were present on the luminal epithelium of PUGKO but not WT uteri. A number of known uterine receptivity genes and gland-specific genes were altered in the PUGKO uterus. Next, the uterus and uterine luminal fluid (ULF) were obtained from WT and PUGKO mice on day 3, 4 and 5. Transcriptome analysis revealed that 580 genes were decreased in the PUGKO uterus, however ULF secrotome analysis revealed that many proteins and several amino acids were increased in the PUGKO ULF. Of note, many proteins encoded by many gland-specific genes were not identified in the ULF of WT mice. These results support the ideas that uterine glands secrete factors that regulate ULF homeostasis and interact with other cell types in the uterus to influence uterine receptivity and blastocyst implantation for the establishment of pregnancy.
2016-11-22 | GSE90101 | GEO
Project description:Glands of the uterus are essential for the establishment of pregnancy in mice, sheep and likely humans. Forkhead box a2 (FOXA2) is expressed specifically in the glands of the uterus and a critical regulator of glandular epithelium (GE) differentiation, development and function. Mice with a conditional deletion of FOXA2 in the adult uterus, created using the lactotransferrin iCre (Ltf-iCre) model, have a morphologically normal uterus with glands, but lack a considerable number of FOXA2-dependent GE-expressed genes. Adult FOXA2 conditional knockout (cKO; Ltf-iCre:Foxa2 flox) mice are infertile due to defective embryo implantation arising from a lack of leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin. Intraperitoneal injections of LIF can initiate embryo implantation in the uterus of adult FOXA2 cKO mice with pregnancies maintained to term. Here, we tested the hypothesis that FOXA2-regulated genes in the uterine glands impact development of the decidua, placenta and fetus. On gestational day (GD) 8.5, the anti-mesometrial and mesometrial decidua transcriptome was noticeably altered in FOXA2 cKO mice. Viable fetuses were reduced in FOXA2 cKO mice on GDs 12.5 and 17.5. Sex-dependent differences in fetal weight, placenta histoarchitecture, and the placenta and metrial gland transcriptome were observed between control and FOXA2 cKO mice. The transcriptome of the placenta with a female fetus was considerably more altered than the placenta with a male fetus in FOXA2 cKO dams. These studies reveal previously unrecognized sexually dimorphic effects of FOXA2 and uterine glands on fetoplacental development with potential impacts on offspring health into adulthood.
2020-07-09 | GSE154026 | GEO
Project description:RNA-seq analysis of uterine luminal epithelium at D4.5 indicates that epithelial PGRA and PGRB shares conseved pathways. Constitutive epithelial PGRA and PGRB disrupts the embryo implantation both through the suppressed FOXO1 signaling by excluding FOXO1 from the nuclear at the uterine epithelium. There are three layers of regulation. Firstly, PGRA and PGRB diminishes Lif transcription in uterine glands by blocking ESR1 binding at the Lif promoter at D3.5 which is critical for the FOXO1 nuclear expression at D4.5 through LIF/pSTAT3/FOXO1. Secondly, PGRA and PGRB directly suppres Foxo1 transcription at the uterine epithelium probably through direct binding at Foxo1 promoter. Thirdly, PGRA and PGRB promotes the Sgk1 transcription, the kinases that phosphorylate FOXO1 to translocate it into cytoplasma for degradation.
2021-12-02 | GSE178541 | GEO