CDX2 dose-dependently influences the GRN underlying vascularization in human extraembryonic mesoderm-like cells
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PROVIDER: PRJNA1055491 | ENA |
REPOSITORIES: ENA
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Project description:Proper regulation of gene dosage is critical for the development of the early embryo and the extraembryonic tissues that support it. Specifically, loss of Cdx2 in vivo leads to stunted development of the allantois, an extraembryonic mesoderm-derived structure that is critical for nutrient delivery and waste removal in the early embryo. In this study, we investigate how CDX2 dose-dependently influences the gene regulatory network underlying extraembryonic mesoderm development. By generating an allelic series for CDX2 in human induced pluripotent stem cells consisting of WT, heterozygous, and null CDX2 genotypes, differentiating these cells in a 2D gastruloid model, and subjecting these cells to multiomic single nucleus RNA and ATAC sequencing, we identify several genes regulating cytoskeletal integrity, adhesiveness, and polarity of the extraembryonic mesoderm and in a dose-dependent manner, including CDH1 and WNT5B. Despite these dose-dependent gene expression patterns, snATAC-seq reveals that heterozygous CDX2 expression is capable of inducing a WT-like chromatin accessibility profile, suggesting accessibility is not sufficient to drive gene expression when the CDX2 dose is reduced. Finally, because the loss of CDX2 or TBXT phenocopy one another in vivo, we compare differentially expressed genes in our CDX2 knock-out model to those from TBXT knock-out hiPSCs differentiated in an analogous experiment. This comparison identifies several genes critical for cytoskeletal integrity and vasculogenesis, including ANK3 and ANGPT1. Taken together, these results inform how CDX2 dose-dependently regulates gene expression in the extraembryonic mesoderm and suggest these genes may underlie defects in vascular development and allantoic elongation seen in the absence or reduction of CDX2 in vivo.
2024-02-14 | GSE251813 | GEO
Project description:Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood–brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.
2022-06-03 | GSE163122 | GEO
Project description:Panicum virgatum GRN Resequencing genome sequencing
| PRJNA334735 | ENA
Project description:The first lineage decisions during mouse development lead to establishment of embryonic and extraembryonic tissues. The transcription factor Cdx2 plays a central role by repressing pluripotency genes, such as Oct4 and promoting trophoblast fate at the blastocyst stage. Here we show that the transcription factor Gata3 is coexpressed with Cdx2 in the blastocyst and that overexpression of Gata3 in embryonic stem cells is sufficient to induce expression of trophoblast genes. Gata3 expression in the blastocyst does not depend on Cdx2, nor do Gata3 overexpressing cell lines require Cdx2 for expression of a subset of trophoblast genes. In the embryo, expression of Gata3, like Cdx2, depends on Tead4, and expression of both factors becomes restricted to nascent trophoblast by an Oct4-independent mechanism. These observations place Tead4 at the top of a trophoblast hierarchy, with Gata3 and Cdx2 acting downstream to induce expression of common and independent targets in this lineage. This SuperSeries is composed of the following subset Series: GSE12985: Differentiation time course of trophoblast stem cells GSE12986: Expression of Cdx2 or Gata3 in R1 mouse embryonic stem cells
2010-02-21 | E-GEOD-12999 | biostudies-arrayexpress
Project description:The first lineage decisions during mouse development lead to establishment of embryonic and extraembryonic tissues. The transcription factor Cdx2 plays a central role by repressing pluripotency genes, such as Oct4 and promoting trophoblast fate at the blastocyst stage. Here we show that the transcription factor Gata3 is coexpressed with Cdx2 in the blastocyst and that overexpression of Gata3 in embryonic stem cells is sufficient to induce expression of trophoblast genes. Gata3 expression in the blastocyst does not depend on Cdx2, nor do Gata3 overexpressing cell lines require Cdx2 for expression of a subset of trophoblast genes. In the embryo, expression of Gata3, like Cdx2, depends on Tead4, and expression of both factors becomes restricted to nascent trophoblast by an Oct4-independent mechanism. These observations place Tead4 at the top of a trophoblast hierarchy, with Gata3 and Cdx2 acting downstream to induce expression of common and independent targets in this lineage. This SuperSeries is composed of the SubSeries listed below.
2010-02-01 | GSE12999 | GEO
Project description:A) Chromatins were prepared from Cdx2-inducible ES cells cultured for 48 - 60 hours in the Dox+ and Dox- conditions. Chromatin immunoprecipitation (ChIP) was carried out by using anti-FLAG M2 affinity gel. ChIP product was tested by Western blotting using anti-FLAG antibody. Nuclear extract from ES cells cultured for 48 - 60 hours in Dox+ and Dox- condition was used for the Western blot. B) CDX2 ChIP-Seq peaks in the Hoxa7 gene region. UCSC Mouse Mm9 browser view of Hoxa7 gene locus after mapping CDX2 ChIP-Seq tags locations in the wiggle format. CDX2 ChIP-Seq peaks are shown in red color. C) Cdx2 ChIP-Seq result was verified by qPCR. Target genes were indicated in (G). Primers flanking a promoter region of Hbb-b1 and Pou5f1 as well as a gene desert region in chromosome 3 were used as negative controls. Primers flanking of Actb gene promoter were used for normalization. The relative enrichment of CDX2 binding was indicated as fold change. (D) CDX2-binding motifs identified with CisFinder using 200 bp sequences centered at ChIP sites. (F) Potential CDX2-direct target genes based on ChIP-Seq and the alteration of expression by Cdx2-overexpression. (G) Identification of CDX2 target genes by combining information on binding sites with gene expression response to Cdx2 over-expression
2009-10-01 | GSE14586 | GEO
Project description:A) Chromatins were prepared from Cdx2-inducible ES cells cultured for 48 - 60 hours in the Dox+ and Dox- conditions. Chromatin immunoprecipitation (ChIP) was carried out by using anti-FLAG M2 affinity gel. ChIP product was tested by Western blotting using anti-FLAG antibody. Nuclear extract from ES cells cultured for 48 - 60 hours in Dox+ and Dox- condition was used for the Western blot. B) CDX2 ChIP-Seq peaks in the Hoxa7 gene region. UCSC Mouse Mm9 browser view of Hoxa7 gene locus after mapping CDX2 ChIP-Seq tags locations in the wiggle format. CDX2 ChIP-Seq peaks are shown in red color. C) Cdx2 ChIP-Seq result was verified by qPCR. Target genes were indicated in (G). Primers flanking a promoter region of Hbb-b1 and Pou5f1 as well as a gene desert region in chromosome 3 were used as negative controls. Primers flanking of Actb gene promoter were used for normalization. The relative enrichment of CDX2 binding was indicated as fold change. (D) CDX2-binding motifs identified with CisFinder using 200 bp sequences centered at ChIP sites. (F) Potential CDX2-direct target genes based on ChIP-Seq and the alteration of expression by Cdx2-overexpression. (G) Identification of CDX2 target genes by combining information on binding sites with gene expression response to Cdx2 over-expression Chromatin IP against CDX2-Flag fusion protein. MC1 ES cells were genetically modified for ROSA26 locus to have Tet-Off expression cassette for C-terminal FLAG tagged Cdx2. The peaks are obtained from the Eland Multi Alignment file. The number of tags in peaks was compared with the number of tags in the control sample for the same region corrected by the total coverage of tags. See supplemental file of the paper for details.
2009-10-01 | E-GEOD-14586 | biostudies-arrayexpress
Project description:Somatic DNA alteration underlies tumor development and progression, and gives rise to tumors with diverse genetic contexts. Here, we identify in a collection of 29 colorectal cancer cell lines and 226 primary colorectal tumors recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor CDX2, a master regulator of anterior-posterior patterning, midgut development, and intestinal epithelial cell differentiation and maintenance. In contrast to its described role as a colorectal tumor suppressor, we show that in the context of genomic amplification, CDX2 is required for proliferation and anchorage-independent growth of colorectal cancer cells. By genome-wide expression and location analysis, we reveal that CDX2 directly promotes expression of Wnt pathway genes. Further results suggest that CDX2 induces expression of intestinal differentiation markers and modulates β-catenin transcriptional activity. These data characterize CDX2 as a novel lineage-survival oncogene deregulated in colorectal cancer. ChIP-seq analysis of CDX2 binding sites in COLO320 cells
2012-11-02 | E-GEOD-30026 | biostudies-arrayexpress
Project description:Somatic DNA alteration underlies tumor development and progression, and gives rise to tumors with diverse genetic contexts. Here, we identify in a collection of 29 colorectal cancer cell lines and 226 primary colorectal tumors recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor CDX2, a master regulator of anterior-posterior patterning, midgut development, and intestinal epithelial cell differentiation and maintenance. In contrast to its described role as a colorectal tumor suppressor, we show that in the context of genomic amplification, CDX2 is required for proliferation and anchorage-independent growth of colorectal cancer cells. By genome-wide expression and location analysis, we reveal that CDX2 directly promotes expression of Wnt pathway genes. Further results suggest that CDX2 induces expression of intestinal differentiation markers and modulates β-catenin transcriptional activity. These data characterize CDX2 as a novel lineage-survival oncogene deregulated in colorectal cancer.
2012-11-02 | GSE30026 | GEO
Project description:Frontotemporal dementia is the second most common form of presenile dementia and autosomal dominant inheritance is present in 20-30% of cases, with mutations in granulin (GRN) as a major cause. The exact pathophysiological mechanism by which GRN mutations lead to neurodegeneration is poorly understood. We aimed to identify novel cerebrospinal fluid (CSF) biomarkers in GRN-associated frontotemporal dementia using shotgun proteomics. We included CSF from presymptomatic and symptomatic GRN mutation carriers and healthy non-carriers (controls). We validated our discovery proteomics results in a large international cohort of GRN-mutation carriers and other forms of genetic FTD (C9orf72- and MAPT-mutation carriers) by parallel reaction monitoring.
2019-04-29 | PXD012179 | Pride