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Stromal Pbrm1 mediates chromatin remodeling necessary for embryo implantation in mouse uterus [ATAC-Seq]

ABSTRACT: Early gestational loss occurs in ~20% of all clinically recognized human pregnancies and is a significant cause of morbidity. Either embryonic or maternal defects can cause loss, but a functioning and receptive uterine endometrium is crucial for embryo implantation. The SWI/SNF remodeling complex containing PBRM1and BRG1 is essential for implantation of the embryonic blastocyst on the wall of the uterus in mice. Although pre-implantation development is unaffected, conditional ablation of Pbrm1 in uterine stromal cells disrupts progesterone pathway and uterine receptivity. Hand2 is a bHLH transcription factor required for embryo implantation. We report a new enhancer of Hand2 in stromal cells that requires PBRM1 for epigenetic histone modifications and coactivator recruitment. In Pbrm1cKO mice, perturbations at the enhancer site compromised Hand2 transcription, disrupts the fibroblast growth factor signaling pathway and prevents normal Stromal- Epithelial crosstalk and embryo implantation. The resultant mutant female mice are infertile and provide insight into potential causes of early pregnancy loss in humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE229367 | GEO | 2024/01/14

REPOSITORIES: GEO

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Stromal Pbrm1 mediates chromatin remodeling necessary for embryo implantation in mouse uterus [RNA-Seq]

Project description:Early gestational loss occurs in ~20% of all clinically recognized human pregnancies and is a significant cause of morbidity. Either embryonic or maternal defects can cause loss, but a functioning and receptive uterine endometrium is crucial for embryo implantation. The SWI/SNF remodeling complex containing PBRM1and BRG1 is essential for implantation of the embryonic blastocyst on the wall of the uterus in mice. Although pre-implantation development is unaffected, conditional ablation of Pbrm1 in uterine stromal cells disrupts progesterone pathway and uterine receptivity. Hand2 is a bHLH transcription factor required for embryo implantation. We report a new enhancer of Hand2 in stromal cells that requires PBRM1 for epigenetic histone modifications and coactivator recruitment. In Pbrm1cKO mice, perturbations at the enhancer site compromised Hand2 transcription, disrupts the fibroblast growth factor signaling pathway and prevents normal Stromal- Epithelial crosstalk and embryo implantation. The resultant mutant female mice are infertile and provide insight into potential causes of early pregnancy loss in humans.

2024-01-14 | GSE229369 | GEO

Stromal Pbrm1 mediates chromatin remodeling necessary for embryo implantation in mouse uterus [CHIC-Seq]

2024-01-14 | GSE229368 | GEO

Gene expression profiling of uterine stromal cells isolated from Hand2 floxed and Hand2 ablated mice on day 4 of pregnancy

Project description:Our previous study revealed that the basic helix-loop-helix transcription factor Hand2 is a downstream target of progesterone signaling in mouse uterine stroma at the time of implantation. Further, conditional deletion of Hand2 in mouse uterus leads to implantation failure due to impaired uterine epithelial receptivity. To identify the downstream targets of Hand2 in the uterus, we performed gene expression profling of uterine stromal cells isolated from Hand2-null mice and the corresponding controls on day4 of pregnancy (the time of implantation). The microarray results revealed elevated expression of mRNAs corresponding to several members of the fibroblast growth factor family in uterine stroma of Hand2-ablated mice. These factors act as paracrine mediators of mitogenic effects of estrogen on the epithleium. Thus, Hand2 is a critical regulator of the uteirne stromal-epithelial communication that directs proper steroid regulation conducive for establshment of pregnancy. We performed conditional ablation of Hand2 in the mouse uterus using the PRcre mouse model. As Hand2 expression is restricted to stromal comaprtment, we isolated uterine stromal cells from day4 pregnant mice (n=5 for each genotype), purified total RNA from these cells, pooled these samples and then hybridized to high density affymetrix microarrays. Control vs. KO.

2011-06-03 | E-GEOD-25881 | biostudies-arrayexpress

Gene expression profiling of uterine stromal cells isolated from Hand2 floxed and Hand2 ablated mice on day 4 of pregnancy

2011-06-03 | GSE25881 | GEO

The analysis of the α2,6-sialylated proteins in endometrium from porcine gestational day 15 by LC-MS/MS

Project description:Implantation is the attachment of embryo in the endometrium. Failure in implantation is a major cause of early pregnancy loss. During implantation, the temporal uterine lumen closure can help embryo attach to the uterus. In pigs, extending of endometrial folds to form interlocking finger-like projections is a main cause leads to uterine lumen closure during attachment time, but the underlying mechanisms are largely unknown. Our data reveal that pig uterine luminal epithelium (LE) migrate in coordinated groups during extending of endometrial folds. Moreover, the MALDI-TOF MS based N-glycomic characterization of porcine endometrium revealed α2,6-linked sialic acid are highly expressed in pig uterine LE during extending of endometrial folds. To investigated the mechanisms by which α2,6-sialylated proteins in formation of the endometrial folding during implantation in pigs, the α2,6-sialylated proteins in pig uterine LE were characterized by proteomic analysis and those proteins that are involved in cell adhesion, such as E-cadherin, were detected. Finally, our in vivo and in vitro data show that α2,6-sialylation of E-cadherin occurs in accompany with collective epithelial migration. The results provide new insight into the mechanism of pig implantation by identifying that α2,6-sialylation of cell adhesion molecules may participate in formation of extending of endometrial folds through promoting of collective migration of uterine LE.

2022-02-17 | PXD027571 | Pride

SOX17 regulates uterine epithelial-stromal crosstalk acting via a distal enhancer upstream of Ihh [ChIP-seq]

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

SOX17 regulates uterine epithelial-stromal crosstalk acting via a distal enhancer upstream of Ihh [array]

2018-08-09 | GSE118264 | GEO

Uterine glands synchronize embryo-endometrial interactions and coordinate on-time embryo implantation and stromal cell decidualization for pregnancy success

Project description:By employing FOXA2-deficient mouse models coupled with LIF repletion, we reveal definitive roles of uterine glands in pregnancy establishment.These studies provide original evidence that uterine glands synchronize embryo-endometrial interactions, coordinate on-time embryo implantation, and impact stromal cell decidualization, thereby ensuring embryo viability, placental growth, and pregnancy success.

2018-04-13 | GSE113065 | GEO

The coregulator, repressor of Estrogen Receptor Activity (REA), is a crucial regulator of the timing and magnitude of uterine decidualization.

Project description:Our findings establish a key role for the coregulator, Repressor of Estrogen receptor Activity (REA), in controlling the timing and magnitude of decidualization in human endometrial stromal cells in vitro and in the mouse uterus in vivo, and suggest that REA functions to synchronize uterine differentiation with concurrent embryo development, which is essential for optimal implantation and fertility. The findings highlight that REA physiologically restrains endometrial stromal cell decidualization, controlling the timing and magnitude of decidualization to enable proper synchronization of uterine differentiation with concurrent embryo development that is essential for implantation and optimal fertility.

2013-04-04 | GSE42376 | GEO

Gene expression profiling of Activin-like kinase 2 knockout in mice

Project description:Implantation of an embryo in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the pregnant uterus, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing uterine-specific Alk2 conditional knockout (cKO) mice. In the absence of ALK2, embryos can invade the uterine epithelium and stroma, but stromal cells cannot undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein Î² (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of C/EBPÎ² to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (HESC) and discovered that ablation of ALK2 alters HESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing HESC confirmed that BMP signaling protein, SMAD1, directly regulates expression of CEBPB by binding a distinct regulatory sequence in the CEBPB promoter; C/EBPÎ², in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate embryo implantation in rodents and primates and, for the first time, uncovers a linear pathwayof BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization. gene expression profiling of two groups: control mice and Alk2 cKO mice

2014-01-07 | E-GEOD-46689 | biostudies-arrayexpress

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