To identify GCM1 novel target genes by chromatin immunoprecipitation-on-chip (ChIP-chip) analysis
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ABSTRACT:
PROVIDER: PRJNA666914 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we performed chromatin immunoprecipitation-on-chip (ChIP-chip) analysis and identified the gene for high-temperature requirement protein A4 (HtrA4) as a GCM1 target gene, which encodes a serine protease facilitating cleavage of fibronectin and invasion of placental cells. Importantly, HtrA4 is immunolocalized in EVTs at the maternal-fetal interface, and its expression is decreased by hypoxia and in preeclampsia, a pregnancy complication associated with placental hypoxia and shallow trophoblast invasion.
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Project description:The placenta develops alongside the embryo and nurtures fetal development to term. During the first stages of embryonic development, due to low blood circulation, the blood and ambient oxygen supply is normally very low (~1-2% O2) and gradually increases upon placental invasion. While a hypoxic environment is associated with stem cell self-renewal and proliferation, persistent hypoxia may have severe effects on differentiating cells and could be the underlying cause of placental disorders. We find that human trophoblast stem cells (TSC) thrive in low oxygen, whereas differentiation of syncytiotrophoblast (STB) and extravillous trophoblast (EVT) is negatively affected by hypoxic conditions. We find that the pro-differentiation factor GCM1 (human Glial Cell Missing-1) is downregulated in low oxygen, and there is substantial reduction of GCM1-regulated genes in hypoxic conditions. Knock-out of GCM1 in TSC caused impaired EVT and STB formation and function, reduced expression of genes that respond to differentiation, and resulted in maintenance of self-renewal genes. Treatment with a PI3K inhibitor reported to reduce GCM1 protein levels likewise counteracts spontaneous or directed differentiation. Chromatin immunoprecipitation of GCM1 showed enrichment of GCM1-specific binding near key transcription factors upregulated upon differentiation including the contact inhibition factor CDKN1C. Loss of GCM1 resulted in downregulation of CDKN1C and corresponding loss of contact inhibition, implicating GCM1 in regulation of this critical process.
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Project description:The placenta develops alongside the embryo and nurtures fetal development to term. During the first stages of embryonic development, due to low blood circulation, the blood and ambient oxygen supply is normally very low (~1-2% O2) and gradually increases upon placental invasion. While a hypoxic environment is associated with stem cell self-renewal and proliferation, persistent hypoxia may have severe effects on differentiating cells and could be the underlying cause of placental disorders. We find that human trophoblast stem cells (TSC) thrive in low oxygen, whereas differentiation of syncytiotrophoblast (STB) and extravillous trophoblast (EVT) is negatively affected by hypoxic conditions. We find that the pro-differentiation factor GCM1 (human Glial Cell Missing-1) is downregulated in low oxygen, and there is substantial reduction of GCM1-regulated genes in hypoxic conditions. Knock-out of GCM1 in TSC caused impaired EVT and STB formation and function, reduced expression of genes that respond to differentiation, and resulted in maintenance of self-renewal genes. Treatment with a PI3K inhibitor reported to reduce GCM1 protein levels likewise counteracts spontaneous or directed differentiation. Chromatin immunoprecipitation of GCM1 showed enrichment of GCM1-specific binding near key transcription factors upregulated upon differentiation including the contact inhibition factor CDKN1C. Loss of GCM1 resulted in downregulation of CDKN1C and corresponding loss of contact inhibition, implicating GCM1 in regulation of this critical process.
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Project description:Wnt signaling plays a major role in early neural development. An aberrant activation in Wnt/β-catenin pathway leads to defective anteroposterior patterning, resulting in neural tube closure defects (NTDs). Changes in folate metabolism may participate in early embryo fate determination. We report here that in C57BL/6C mouse embryonic stem cells (mESC), folate deficiency activates Wnt/β-catenin pathway by upregulating a chorion-specific transcription factor Gcm1. Specifically, folate deficiency promotes the formation of the Gcm1/β-catenin/T-cell factor (TCF4) complex to regulate the Wnt target gene transactivation through the Wnt-responsive elements. Moreover, the enhanced transcriptional activity of Gcm1 is found to be dependent on CREB binding protein. Lastly, in NTDs mouse models and low folate NTDs human brain samples, Gcm1 and Wnt/β-catenin target genes related to neural tube closure are specifically overexpressed. These results indicate that low folate promotes Wnt/β-catenin signaling via activating Gcm1, leading to aberrant vertebrate neural development
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Project description:The placenta develops alongside the embryo and nurtures fetal development to term. During the first stages of embryonic development, due to low blood circulation, the blood and ambient oxygen supply is normally very low (~1-2% O2) and gradually increases upon placental invasion. While a hypoxic environment is associated with stem cell self-renewal and proliferation, persistent hypoxia may have severe effects on differentiating cells and could be the underlying cause of placental disorders. We find that human trophoblast stem cells (TSC) thrive in low oxygen, whereas differentiation of syncytiotrophoblast (STB) and extravillous trophoblast (EVT) is negatively affected by hypoxic conditions. We find that the pro-differentiation factor GCM1 (human Glial Cell Missing-1) is downregulated in low oxygen, and there is substantial reduction of GCM1-regulated genes in hypoxic conditions. Knock-out of GCM1 in TSC caused impaired EVT and STB formation and function, reduced expression of genes that respond to differentiation, and resulted in maintenance of self-renewal genes. Treatment with a PI3K inhibitor reported to reduce GCM1 protein levels likewise counteracts spontaneous or directed differentiation. Chromatin immunoprecipitation of GCM1 showed enrichment of GCM1-specific binding near key transcription factors upregulated upon differentiation including the contact inhibition factor CDKN1C. Loss of GCM1 resulted in downregulation of CDKN1C and corresponding loss of contact inhibition, implicating GCM1 in regulation of this critical process.
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Project description:The placenta develops alongside the embryo and nurtures fetal development to term. During the first stages of embryonic development, due to low blood circulation, the blood and ambient oxygen supply is normally very low (~1-2% O2) and gradually increases upon placental invasion. While a hypoxic environment is associated with stem cell self-renewal and proliferation, persistent hypoxia may have severe effects on differentiating cells and could be the underlying cause of placental disorders. We find that human trophoblast stem cells (TSC) thrive in low oxygen, whereas differentiation of syncytiotrophoblast (STB) and extravillous trophoblast (EVT) is negatively affected by hypoxic conditions. We find that the pro-differentiation factor GCM1 (human Glial Cell Missing-1) is downregulated in low oxygen, and there is substantial reduction of GCM1-regulated genes in hypoxic conditions. Knock-out of GCM1 in TSC caused impaired EVT and STB formation and function, reduced expression of genes that respond to differentiation, and resulted in maintenance of self-renewal genes. Treatment with a PI3K inhibitor reported to reduce GCM1 protein levels likewise counteracts spontaneous or directed differentiation. Chromatin immunoprecipitation of GCM1 showed enrichment of GCM1-specific binding near key transcription factors upregulated upon differentiation including the contact inhibition factor CDKN1C. Loss of GCM1 resulted in downregulation of CDKN1C and corresponding loss of contact inhibition, implicating GCM1 in regulation of this critical process.
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Project description:Human trophoblast stem cells were infected with lentivirus to knockdown the transcription factor GCM1. RNA-seq was then utilized to determine global transcriptomic changes between control and GCM1-deficient human trophoblasts either cultured as cytotrophoblasts or induced to form extravillous trophoblasts. This study provides insight into the molecular mechanisms regulating extavillous trophoblast development.
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Project description:The global physiological effects of glucocorticoids are well established, and the framework of transcriptional regulation by the glucocorticoid receptor (GR) has been described. However, the genes directly under GR control that trigger these physiological effects are largely unknown. To address this issue in a single cell type, we identified glucocorticoid-responsive genes in A549 human lung adenocarcinoma cells by microarray analysis and quantitative real-time PCR. Reduction of GR expression by RNA interference diminished the effects of dexamethasone on all tested target genes, thus confirming the essential role of GR in glucocorticoid-regulated gene expression. To identify primary GR target genes, in which GR is a component of the transcriptional regulatory complex, we developed a strategy that uses chromatin immunoprecipitation to scan putative regulatory regions of target genes for sites occupied by specifically bound GR. We screened 11 glucocorticoid-regulated genes, and we identified GR-binding regions for eight of them (five induced and three repressed). Thus, our approach provides a means for rapid identification of primary GR target genes and glucocorticoid-response elements, which will facilitate analyses of transcriptional regulatory mechanisms and determination of hormone-regulated gene networks.
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