TET1 modulates trophoblast function by regulation of ODC1 in preeclampsia
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PROVIDER: PRJNA1285788 | ENA |
REPOSITORIES: ENA
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Project description:Analysis of trophoblast cell line HTR8/SVneo knocking down the DNA hydroxymethylase TET1. The results provide insights into genes that undergo expression changes in trophoblast cells due to DNA hydroxymethylation.
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Project description:Placentation requires the proper regulation of extravillous trophoblast (EVT) migration and invasion into the decidua and maternal vasculature, processes which are initiated in physiologic hypoxic conditions. Abnormal EVT migration and/or invasion have been suggested to lead to pregnancy complications, such as preeclampsia. The objectives of this study are to determine how exposure to hypoxia impacts gene expression and cellular motility of first trimester trophoblasts, and to assess if expression of migration-associated genes is dysregulated in 2nd trimester chorionic villous samples (CVS) from preeclampsia pregnancies relative to CVS from healthy pregnancies. The 1st trimester trophoblast cell line, HTR8/SVneo, was used to investigate the relationship between hypoxia and Notch signaling in trophoblast migration and invasion. RNA sequencing and quantitative RT-PCR analyses show that exposure to hypoxia (2.5% O2) activates Notch signaling in HTR-8/SVneo. We demonstrate that exposure of HTR-8/SVneo to hypoxia induces expression of genes associated with cellular migration and invasion and increases HTR-8/SVneo cellular migration and invasion, whereas inhibition of gamma-secretase decreases Notch signaling and decreases HTR-8/SVneo migration and invasion. Analysis of RNA sequencing data from CVS of preeclampsia and uncomplicated pregnancies identified significant differentially expressed genes that are involved in cellular migration and invasion. Decreased expression of migration and invasion genes in CVS from preeclampsia pregnancies, may impair trophoblast migration and invasion in the 2nd trimester of pregnancy, resulting in the development of preeclampsia.
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Project description:The ten-eleven translocation (Tet) proteins are well known for their role in maintaining naive pluripotency of embryonic stem cells. Here, we demonstrate that jointly, Tet1 and Tet2 also safeguard the self-renewal potential of trophoblast stem cells (TSCs) and have partially redundant roles in maintaining their epithelial integrity. For the more abundantly expressed Tet1, we demonstrate that this is achieved by binding to critical epithelial genes, notably E-Cadherin, which becomes hyper-methylated and down-regulated in the absence of Tet1. This epithelial-to-mesenchymal transition phenotype is accompanied by centrosome duplication and separation defects. Moreover, we identify a novel role of Tet1 in stabilizing Cyclin B1, thereby acting as a facilitator of mitotic cell cycle progression. As a result, Tet1/2 mutant TSCs are prone to undergo endoreduplicative cell cycles leading to the formation of polyploid trophoblast giant cells. Taken together, our data reveal essential functions of Tet proteins in the trophoblast lineage.
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Project description:The maternal signs of preeclampsia, principally the new onset of high blood pressure, are thought to occur secondary to faulty placentation. Previous studies profiled the gene expression patterns of chorionic villi, the maternal-fetal interface or isolated cytotrophoblasts in this pregnancy complication. We theorized that transcriptomic analyses of trophoblast subpopulations in situ would give us new insights into the role of these cells in preeclampsia pathogenesis.
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Project description:Successful placentation requires delicate communication between endometrium and trophoblasts. The invasion and integration of trophoblasts into the endometrium during early pregnancy is crucial to placentation. Dysregulation of these functions is associated with various pregnancy complications such as miscarriage and preeclampsia. The endometrial microenvironment exerts an important influence on trophoblast cell functions. We hypothesized that the hormonal environment regulates the miRNA profile and secretome of the human endometrial gland, which subsequently modulates trophoblast functions during early pregnancy. By establishing the first secretome profiles and miRNA atlas of these endometrial organoids to the hormonal changes followed by trophoblast functional assays, we demonstrated that sex steroid hormones modulate aquaporins (AQP)1/9 and S100A9 secretions through miR-3194 activation in endometrial epithelial cells, which in turn enhanced trophoblast migration and invasion during early pregnancy.
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Project description:To explore the potential role of focal adhesion kinase (FAK) in trophoblast functions in early-onset preeclampsia (EOPE).We first examined expression and localization in placental tissue as well as in villus tissue during early pregnancy. Then, FAK activity was inhibited with Y15. The effects of FAK on the invasion and proliferation of trophoblast cells (HTR8/SVneo) were investigated. Transcriptomic and bioinformatics analyses were then used to predict the possible pathways by which FAK is involved in PE. Finally, we measured the expression of FAK in a PE mouse model. Transcriptomic and bioinformatics results suggest that Rap1 may be a downstream regulator of trophoblast FAK. In mouse models, we found reduced expression of FAK and Rap1 in the placenta of PE mice.
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Project description:Preeclampsia (PE) is a hypertensive pregnancy disorder with increased risk of maternal and fetal morbidity and mortality. Abnormal extravillous trophoblast (EVT) development and function is considered to be the underlying cause of PE, but has not previously been modeled in vitro. We previously derived induced pluripotent stem cells (iPSC) from placentas of PE patients and characterized abnormalities in formation of syncytiotrophoblast and responses to changes in oxygen tension. In this study, we converted these primed iPSC to naïve iPSC, then derived trophoblast stem cells (TSC) and EVT to evaluate molecular mechanisms underlying PE. We found that primed (but not naïve) iPSC-derived PE-EVT have reduced surface HLA-G, blunted invasive capacity, and altered EVT-specific gene expression. These abnormalities correlated with promotor hypermethylation of genes associated with the epithelial-mesenchymal transition pathway, specifically in primed-iPSC derived PE-EVT. Our findings indicate that abnormal epigenetic regulation might play a role in the PE pathogenesis.
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Project description:Early onset preeclampsia (EOPE) affects about 0.4% of pregnancies and is characterized by impaired trophoblast (TB) invasion, resulting in a poorly perfused placenta. Here we have used an in vitro model for mimicking early trophoblast development to determine how early placental development differs between normal pregnancies and those affected by EOPE. Induced pluripotent stem cells (iPSC) were generated from umbilical cords of infants born to mothers who had EOPE and from controls. These iPSC were converted to TB, by exposing them to BMP4 and inhibitors of ACTIVIN A and FGF2 signaling (BAP treatment), under 5 % and 20 % O2, hypothesizing that 20% O2 would act as a stressor. Two embryonic stem cell lines (ESC; H1 and H9), 8 control (CTL) iPSC and 14 EOPE iPSC were tested to assess how well the differentiated TB cells invaded through a Matrigel-coated membrane.
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