Myostatin Increases Trophoblast Cell Invasion Through Regulating Epithelial Mesenchymal Transition Genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA935369 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23478409_1.fastq.gz | Fastqsanger.gz | |||
| SRR23478409_2.fastq.gz | Fastqsanger.gz | |||
| SRR23478410_1.fastq.gz | Fastqsanger.gz | |||
| SRR23478410_2.fastq.gz | Fastqsanger.gz | |||
| SRR23478411_1.fastq.gz | Fastqsanger.gz |
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Project description:Myostatin (MSTN) is a TGF-β superfamily member and was recently shown to be secreted and functioning in the placenta. In this study, we perfomed mRNA sequencing on control and MSTN-treated primary trophoblast cells to decipher the underlying molecular mechanisms involved in MSTN-induced human trophoblast cell invasion.
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Project description:The phenotype of term, human placental extravillous trophoblast (EVT) reflects both the first trimester differentiation from villous cytotrophoblast (CTB) and later gestational changes, including the loss of proliferative and invasive capacity. Invasion abnormalities, as observed in preeclampsia and placenta accreta spectrum, are not usually diagnosed until the second or even third trimester of pregnancy. Characterization of the normal processes at term, including arrest of invasion is therefore crucial. In this report gene expression analysis demonstrates definitively the epithelial-mesenchymal transition (EMT) mechanism which underlies differentiation and provides a trophoblast-specific EMT signature. Methylation profiling shows that CTB, already hypomethylated relative to other somatic cells, show a further degree of hypomethylation in their transition to EVT. A small fraction of genes show both gain of methylation and changes in gene expression. Prominent are genes involved in the EMT such as the transcription factor RUNX1, loss of which leads to reduced migratory capacity in JEG3 trophoblast cells. Examination of these EMT genes leads us to suggest that the gains of methylation may assist in maintaining term EVT in a mesenchymal but non-invasive state.
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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:Vascular endothelial (VE-)cadherin is a homotypic adhesion protein that is expressed selectively by ECs in which it enables formation of tight vessels and regulation of vascular permeability. Since VE-cadherin is also strongly expressed in placental trophoblasts, it is a prime candidate for a molecular mechanism of vascular mimicry by those cells. Here, we show that the VE-cadherin is required for trophoblast migration and endovascular invasion into the maternal decidua. VE-cadherin deficiency results in loss of spiral artery remodeling due to a lack of invasive trophoblasts, leading to decreased flow of maternal blood into the placenta, fetal growth retardation and death. Loss of trophoblast invasion prevents decidualization, extracellular matrix remodeling, and immune cell clearance. These studies identify VE-cadherin as essential for trophoblast migration and coordination of decidual changes during endovascular invasion. They further suggest endothelial proteins such as VE-cadherin that are expressed by trophoblasts may play functionally distinct roles that do not simply mimic those in ECs.
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Project description:The phenotype of term, human placental extravillous trophoblast (EVT) reflects both the first trimester differentiation from villous cytotrophoblast (CTB) and later gestational changes, including the loss of proliferative and invasive capacity. Invasion abnormalities, as observed in preeclampsia and placenta accreta spectrum, are not usually diagnosed until the second or even third trimester of pregnancy. Characterization of the normal processes at term, including arrest of invasion is therefore crucial. In this report gene expression analysis demonstrates definitively the epithelial-mesenchymal transition (EMT) mechanism which underlies differentiation and provides a trophoblast-specific EMT signature. Methylation profiling shows that CTB, already hypomethylated relative to other somatic cells, show a further degree of hypomethylation in their transition to EVT. A small fraction of genes show both gain of methylation and changes in gene expression. Prominent are genes involved in the EMT such as the transcription factor RUNX1, loss of which leads to reduced migratory capacity in JEG3 trophoblast cells. Examination of these EMT genes leads us to suggest that the gains of methylation may assist in maintaining term EVT in a mesenchymal but non-invasive state.
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Project description:Uterine Natural Killer (uNK) cells regulate essential developmental processes at the maternal-fetal interface during early pregnancy. Uterine NK cell functions are tightly regulated during early placentation to stimulate trophoblast invasion and remodel uterine spiral arteries. Access to human 1st and 2nd trimester uterine tissues allowed us to investigate the transcriptional changes in uNK cells during the early stages of early human pregnancy. Microarray analysis identified 97 upregulated genes in 2nd compared to 1st trimester purified uNK cells of which the majority (61%) clustered as interferon-stimulated-genes (ISG), with ISG15 and ISG20 being upregulated profoundly. Type I interferons (IFNα/β), but not type II interferon (IFNɣ) increased expression of the identified interferon target genes ISG15 and ISG20 in uNK cells in vitro. Moreover, the cytokine-like protein ISG15 stimulated in vitro trophoblast invasion. Second trimester uNK cells promoted trophoblast invasion in vitro, whereas both 1st and 2nd trimester uNK cells stimulated endothelial tube formation. IFNα but not IFNβ stimulation of 1st trimester uNK cells enhanced their capacity to promote trophoblast invasion. In conclusion, the uNK cell interferon transcriptome is upregulated during the 2nd trimester allowing uNK cells to promote trophoblast invasion. Type I interferon signaling regulates uNK cell-induced trophoblast invasion via induction of effector molecules like ISG15. First trimester uNK cells can be induced to act like second trimester uNK cells by IFNα with respect to promotion of trophoblast invasion. Key words: Gene expression profiling ■ uterine natural killer cells ■ extravillous trophoblast invasion ■ interferon alpha ■ ISG15
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Project description:YY1 is a sequence-specific DNA-binding transcription factor that has many important biological roles. However, its function in trophoblasts at the maternal-foetal interface remains to be elucidated. In this study, we used an mRNA microarray and quantitative reverse transcription-PCR and compared the YY1 mRNA expression level in trophoblasts between patients with recurrent miscarriage (RM) and healthy control subjects. Our results revealed that YY1 mRNA expression was significantly lower in the trophoblasts of the RM group compared with the healthy control group. Furthermore, immunofluorescence and immunohistochemical data showed that YY1 was highly expressed in human placental villi during early pregnancy, especially in cytotrophoblast cells and invasive extravillous trophoblasts, and it was expressed at a much lower level in the placental villi of term pregnancy. YY1 overexpression enhanced the invasion and proliferation of trophoblasts, while knockdown of YY1 repressed these effects. Antibody array screening revealed that YY1 significantly promoted MMP2 expression in trophoblasts. Bioinformatics analysis identified three YY1-binding sites in the MMP2 promoter region, and chromatin immunoprecipitation analysis verified that YY1 binds directly to its promoter region. Importantly, inhibition of YY1 by siRNA clearly decreased trophoblast invasion in an ex vivo explant culture model. Overall, our findings revealed a new regulatory pathway of YY1/MMP2 in trophoblast cells invasion during early pregnancy, and indicated that YY1 may be involved in the pathogenesis of RM. Total RNA was isolated using Trizol from trophoblast cells from three healthy controls (HC) and three recurrent miscarriage (RM) patients. Total RNA were extracted and used for hybridizing Affymetrix chips (GeneChip® Human Transcriptome Array 2.0(HTA2.0)). Data were normalised by gcRMA method and raw p-values adjusted by Bonferroni procedure (1%).
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Project description:The placenta is an understudied organ that has a critical role in mammalian development. In early placental development, the essential process of trophoblast invasion establishes adequate blood flow between mother and fetus. Despite its importance, little is known about the genomic regions responsible for regulating trophoblast invasion. In order to identify enhancers that are important for regulating the process, we carried out ChIP-Seq for an enhancer-associated mark at two time points during early placental development. Combining these data with RNA-Seq data and protein interaction data allowed us to construct a gene-enhancer network describing trophoblast invasion.
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Project description:The placenta is an understudied organ that has a critical role in mammalian development. In early placental development, the essential process of trophoblast invasion establishes adequate blood flow between mother and fetus. Despite its importance, little is known about the genomic regions responsible for regulating trophoblast invasion. In order to identify enhancers that are important for regulating the process, we carried out ChIP-Seq for an enhancer-associated mark at two time points during early placental development. Combining these data with RNA-Seq data and protein interaction data allowed us to construct a gene-enhancer network describing trophoblast invasion.
2015-12-01 | GSE65807 | GEO
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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