SOX17 regulates uterine epithelial-stromal crosstalk acting via a distal enhancer upstream of Ihh [array]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE118264 | GEO | 2018/08/09
REPOSITORIES: GEO
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Project description:Mammalian embryo development is dependent on the ability of the uterus to allow and support the implantation of the embryo. Here we demonstrate that ablation of Sox17 specifically in the uterine epithelium results in altered uterine epithelial cell proliferation, uterine gland development and embryo implantation. Uteri lacking Sox17 showed reduction in LIF and IHH signaling which are critical for embryo implantation. ChIP-seq analysis demonstrated that SOX17 binds to a region 19kb 5’ to the Ihh locus. In vivo deletion of this enhancer by the CRISPR-Cas technology reduced Ihh expression in uteri and altered proper endometrial epithelial-stromal interactions required for pregnancy leading to compromised fertility. The SOX17 binding peak at 19kb from the Ihh promoter also bound GATA2, FOXA2 and PGR. Bioinformatic analysis of regions overlapping SOX17, GATA2, FOXA2 and PGR bindings shows 737 genes with these common binding sites. This cluster of transcription factors identified in this enhancer region may represent a combination of regulatory elements essential for uterine epithelial gene expression and differentiation.
2018-08-09 | GSE118327 | 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: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:The mammalian endometrium is covered by the luminal epithelium (Le), which directly interacts with the blastocyst and plays an important role in the establishment of reciprocal crosstalk between the embryo and receptive uterus during implantation. However, the effect of the blastocyst on uterine receptivity is far from well understood. Through transcriptomic profiling of the uterine Le isolated by laser capture microdissection, it was demonstrated that global gene expression changes occurred in Le between pseudopregnant mice without embryos and pregnant mice with embryos. Some differentially expressed genes, including upregulated Areg, Ihh, Lifr and downregulated Msx1, Pgr, Gata2, have been reported to regulate the establishment of uterine receptivity. Besides, we found that blastocysts induced an increase in both the number and acidification of lysosome, consistent with enhanced lysosomal hydrolase activity in uterine Le. Further exploration uncovered that blastocyst-derived IGF2 was involved into the activation of epithelial STAT3 to induce lysosomal hydrolase expression, and inhibition of lysosomal function derails normal uterine receptivity and embryo implantation. Finally, based on the proteomic data of both epithelia and the separated lysosome, it was revealed that CLDN1 and MUC1, two well-known downregulated molecules for successful implantation, are degraded by epithelial lysosome. In brief, our data demonstrated that blastocysts induced normal epithelium differentiation with lysosome activation to promote the establishment of uterine receptivity for embryo implantation.
2024-01-10 | GSE231827 | GEO
Project description:The mammalian endometrium is covered by the luminal epithelium (Le), which directly interacts with the blastocyst and plays an important role in the establishment of reciprocal crosstalk between the embryo and receptive uterus during implantation. However, the effect of the blastocyst on uterine receptivity is far from well understood. Through transcriptomic profiling of the uterine Le isolated by laser capture microdissection, it was demonstrated that global gene expression changes occurred in Le between pseudopregnant mice without embryos and pregnant mice with embryos. Some differentially expressed genes, including upregulated Areg, Ihh, Lifr and downregulated Msx1, Pgr, Gata2, have been reported to regulate the establishment of uterine receptivity. Besides, we found that blastocysts induced an increase in both the number and acidification of lysosome, consistent with enhanced lysosomal hydrolase activity in uterine Le. Further exploration uncovered that blastocyst-derived IGF2 was involved into the activation of epithelial STAT3 to induce lysosomal hydrolase expression, and inhibition of lysosomal function derails normal uterine receptivity and embryo implantation. Finally, based on the proteomic data of both epithelia and the separated lysosome, it was revealed that CLDN1 and MUC1, two well-known downregulated molecules for successful implantation, are degraded by epithelial lysosome. In brief, our data demonstrated that blastocysts induced normal epithelium differentiation with lysosome activation to promote the establishment of uterine receptivity for embryo implantation.
2024-01-10 | GSE231826 | GEO
Project description:We generated mice with single or double conditional inactivation of SMAD1 and SMAD5 using progesterone receptor (PR) cre (Smad1flox/flox;Smad5flox/flox;Pgr-cre+/-, or “Smad1/5 cKO”). Female mice with single SMAD1 or SMAD5 deletion were subfertile, whereas Smad1/5 cKO were infertile and had no visible implantation sites at 4.5 days post-coitum (dpc), indicating functional redundancy of SMAD1 and SMAD5. Histological and molecular analyses of the Smad1/5 cKO uteri during pregnancy determined that the infertility was the result of impaired uterine receptivity. During the window of implantation, uteri of Smad1/5 cKO mice responded abnormally to estradiol (E2) and to progesterone (P4), retained luminal PR expression, and displayed cytoplasmic FOXO1 mis-localization. Furthermore, uteri of Smad1/5 cKO mice did not respond to an artificial decidual stimulus and the stroma failed to differentiate. To determine the cell surface receptor complex that controls BMP signaling during implantation, we generated mice with conditional deletion of Acvr2a and Acvr2b using Pgr-cre+/-. We determined that Acvr2b cKO females were subfertile, while Acvr2a cKOs were infertile and displayed a range of ovarian and uterine abnormalities, including endometrial and implantation defects that phenocopied those of Smad1/5 cKO mice. Transcriptomic profiling of the Smad1/5 cKO and Acvr2a cKO uterus showed that genes involved in epithelial cell remodeling and microvilli/ciliated cell function were overrepresented in both genotypes. These results demonstrate that BMP signals mediated via ACVR2A and SMAD1/5 control endometrial receptivity and embryo implantation by remodeling the apicobasal polarity of the epithelium during the window of implantation.
2021-04-23 | GSE152675 | GEO
Project description:Conditional ablation of Indian hedgehog (Ihh) in the murine uterus results in mice that are sterile due to defects in embryo implantation. We performed microarray analysis on these mice at the time point at which the Ihh target genes are induced by the administration of exogenous hormone to mimic day 3.5 of pregnancy. This analysis identified 863 genes altered by the conditional ablation of Ihh. Of these, genes that regulated the cell cycle were overrepresented. In addition, genes involved in epidermal growth factor (EGF) and estrogen (E2) signaling were found to be deregulated upon Ihh ablation. Furthermore, upon conditional ablation of Ihh, 15 month old mice exhibited hallmarks of estrogenized uteri such as cystically dilated glands and hyalinized stroma. Thus, Ihh regulates embryo implantation by impacting the cell cycle, EGF signaling, and E2 signaling. Keywords: two group comparison We conditionally ablated Indian hedgehog in the mouse uterus using the PRcre mouse model (PRcre/+Ihhf/f; Ihhd/d). High density DNA microarray analysis was performed on Day -1 of the artificial decidual response on Ihhf/f and Ihhd/d uteri.
2010-03-06 | E-GEOD-19517 | biostudies-arrayexpress
Project description:Conditional ablation of Indian hedgehog (Ihh) in the murine uterus results in mice that are sterile due to defects in embryo implantation. We performed microarray analysis on these mice at the time point at which the Ihh target genes are induced by the administration of exogenous hormone to mimic day 3.5 of pregnancy. This analysis identified 863 genes altered by the conditional ablation of Ihh. Of these, genes that regulated the cell cycle were overrepresented. In addition, genes involved in epidermal growth factor (EGF) and estrogen (E2) signaling were found to be deregulated upon Ihh ablation. Furthermore, upon conditional ablation of Ihh, 15 month old mice exhibited hallmarks of estrogenized uteri such as cystically dilated glands and hyalinized stroma. Thus, Ihh regulates embryo implantation by impacting the cell cycle, EGF signaling, and E2 signaling. Keywords: two group comparison
2010-03-01 | GSE19517 | GEO
Project description:The role of Gata2 in regulating uterine function including fertility, implantation, decidualization and P4 signaling in the mouse was investigated by the conditional ablation of Gata2 in the uterus using the (PR-cre) mouse and ChIP-seq for in vivo GATA2 binding sites in the murine uterus upon acute P4 administration. Gata2 gene ablation was confirmed by real-time PCR analysis in the PR-cre; Gata2fl/fl (termed Gata2d/d) uterus. While littermate controls are fertile, Gata2d/d females are completely infertile. Analysis of the infertility indicates that implantation does not occur, and the uterine stroma is incapable of undergoing the decidual reaction to support further embryonic development. Measure of P4 target genes including PR itself indicate a block in P4 target gene induction and that Gata2 regulates PR expression directly. Microarray analysis demonstrates that ablation of Gata2 leads to specific gene changes, including disruption of the Wnt signaling pathway, Progesterone receptor (PR) signaling, and Ihh signaling pathway. In addition we identified 46,183 GATA2 binding sites in P4 treatment conditions with 7,954 binding sites overlapping that of the PR.Taken together, these data demonstrate that Gata2 is a critical regulator of gene expression and function in the murine uterus.
2014-01-01 | E-GEOD-40659 | biostudies-arrayexpress
Project description:The role of Gata2 in regulating uterine function including fertility, implantation, decidualization and P4 signaling in the mouse was investigated by the conditional ablation of Gata2 in the uterus using the (PR-cre) mouse and ChIP-seq for in vivo GATA2 binding sites in the murine uterus upon acute P4 administration. Gata2 gene ablation was confirmed by real-time PCR analysis in the PR-cre; Gata2fl/fl (termed Gata2d/d) uterus. While littermate controls are fertile, Gata2d/d females are completely infertile. Analysis of the infertility indicates that implantation does not occur, and the uterine stroma is incapable of undergoing the decidual reaction to support further embryonic development. Measure of P4 target genes including PR itself indicate a block in P4 target gene induction and that Gata2 regulates PR expression directly. Microarray analysis demonstrates that ablation of Gata2 leads to specific gene changes, including disruption of the Wnt signaling pathway, Progesterone receptor (PR) signaling, and Ihh signaling pathway. In addition we identified 46,183 GATA2 binding sites in P4 treatment conditions with 7,954 binding sites overlapping that of the PR.Taken together, these data demonstrate that Gata2 is a critical regulator of gene expression and function in the murine uterus.
2014-01-01 | E-GEOD-40660 | biostudies-arrayexpress