Transcriptomic analysis of embryonic hearts with conditional deletion of Wt1
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE178220 | GEO | 2021/07/10
REPOSITORIES: GEO
Similar Datasets
Project description:Transcriptomic analysis of embryonic hearts with conditional deletion of Wt1
| PRJNA737788 | ENA
Project description:Coronary blood vessel formation is a highly regulated process in which endothelial cells (ECs) play an essential role. During the last years, new pieces of evidence have demonstrated WT1 expression in coronary ECs. However, its role in coronary blood vessel formation was almost unknown. Here we generated an inducible endothelial-specific Wt1KO mouse model (Wt1KOΔEC). The analysis of these mutant mice has demonstrated that deletion of Wt1 in coronary ECs impairs coronary blood vessels and myocardium development. The transcriptomic analysis of coronary ECs from Wt1KOΔEC mice demonstrated that deletion of Wt1 has a great impact on the molecular signature of coronary ECs that correlate with defects in cell proliferation, migration, and differentiation. These results provide novel insights into the role of WT1 in heart development and demonstrate that WT1 in ECs is required for coronary blood vessel formation.
2023-02-22 | GSE205616 | GEO
Project description:Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1. Experiment Overall Design: Identification of WNT/Beta-Catenin or WT1 target genes. 39 individual samples.
2008-06-14 | E-GEOD-6120 | biostudies-arrayexpress
Project description:K-ras is one of the most frequently mutated human oncogenes. Activation of K-ras can lead to either senescence or proliferation in primary cells. The precise mechanism governing these distinct outcomes remains unclear. Here we utilized a loss-of-function screen to assess the role of specific genes identified as potential key regulators of K-ras driven oncogenesis. Using this approach, we identify the transcription factor Wt1 as an inhibitor of senescence in primary cells expressing oncogenic K-ras. Deletion or suppression of Wt1 expression leads to senescence of primary cells expressing oncogenic K-ras under the control of the native promotor at physiological levels, but has no effect on cells expressing wild-type K-ras. Wt1 contributes to K-ras driven lung tumorigenesis in vivo and loss of Wt1 is specifically deleterious to human lung cancer cell lines that are dependent on oncogenic K-ras. Taken together, these observations reveal a novel role for Wt1 as a key regulator of the complex genetic network required for the oncogenic effect of the small GTPase K-ras. We compare the expression profiles of Wild type, K-ras mutant, Wt1-null, and double K-ras mutant/Wt1-null mouse embryonic fibroblasts (MEFs). The study provides insights into the transcriptional role of Wt1 in the context of oncogenic K-ras.
2010-03-01 | GSE15325 | GEO
Project description:During cardiac development, cells from the precardiac mesoderm fuse to form the primordial heart tube, which then grows by addition of further progenitors to the venous and arterial poles. In the zebrafish, wilms tumor 1 transcription factor a (wt1a) and b (wt1b) are expressed in the pericardial mesoderm at the venous pole of the forming heart tube. The pericardial mesoderm forms a single layered mesothelial sheet that contributes to further the growth of the myocardium, and forms the proepicardium. Proepicardial cells are subsequently transferred to the myocardial surface and give rise to the epicardium, the outer layer covering the myocardium in the adult heart. wt1a/b expression is downregulated during the transition from pericardium to myocardium, but remains high in proepicardial cells. Here we show that sustained wt1 expression impaired cardiomyocyte maturation including sarcomere assembly, ultimately affecting heart morphology and cardiac function. ATAC-seq data analysis of cardiomyocytes overexpressing wt1 revealed that chromatin regions associated with myocardial differentiation genes remain closed upon wt1b overexpression in cardiomyocytes, suggesting that wt1 represses a myocardial differentiation program. Indeed, a subset of wt1a/b-expressing cardiomyocytes changed their cell adhesion properties, delaminated from the myocardial epithelium, and upregulated the expression of epicardial genes, as confirmed by in vivo imaging. Thus, we conclude that wt1 acts as a break for cardiomyocyte differentiation by repressing chromatin opening at specific genomic loci and that sustained ectopic expression of wt1 in cardiomyocytes can lead to their transformation into epicardial cells.
2022-03-08 | GSE179520 | GEO
Project description:During cardiac development, cells from the precardiac mesoderm fuse to form the primordial heart tube, which then grows by addition of further progenitors to the venous and arterial poles. In the zebrafish, wilms tumor 1 transcription factor a (wt1a) and b (wt1b) are expressed in the pericardial mesoderm at the venous pole of the forming heart tube. The pericardial mesoderm forms a single layered mesothelial sheet that contributes to further the growth of the myocardium, and forms the proepicardium. Proepicardial cells are subsequently transferred to the myocardial surface and give rise to the epicardium, the outer layer covering the myocardium in the adult heart. wt1a/b expression is downregulated during the transition from pericardium to myocardium, but remains high in proepicardial cells. Here we show that sustained wt1 expression impaired cardiomyocyte maturation including sarcomere assembly, ultimately affecting heart morphology and cardiac function. ATAC-seq data analysis of cardiomyocytes overexpressing wt1 revealed that chromatin regions associated with myocardial differentiation genes remain closed upon wt1b overexpression in cardiomyocytes, suggesting that wt1 represses a myocardial differentiation program. Indeed, a subset of wt1a/b-expressing cardiomyocytes changed their cell adhesion properties, delaminated from the myocardial epithelium, and upregulated the expression of epicardial genes, as confirmed by in vivo imaging. Thus, we conclude that wt1 acts as a break for cardiomyocyte differentiation by repressing chromatin opening at specific genomic loci and that sustained ectopic expression of wt1 in cardiomyocytes can lead to their transformation into epicardial cells.
2022-03-08 | GSE179521 | GEO
Project description:Wt1 is required for renal development and homozyogus knockout mice show renal agenesis caused by apoptosis of the metanepric mesnchyme. To identify genes regulated by WT1, we performed comparative gene expression profiling on kidney rudmients of Wt1 heterozygous and homozygous mutant E10.25 embryos.
2014-06-01 | GSE58073 | GEO
Project description:K-ras is one of the most frequently mutated human oncogenes. However, activation of K-ras can lead to either senescence or proliferation in primary cells. The precise mechanism governing these distinct outcomes remains unclear. Here we describe a novel loss-of-function screen to assess the role of specific genes identified as potential key regulators of K-ras driven oncogenesis. Using this approach, we identify the transcription factor Wt1 as an inhibitor of senescence in primary cells expressing oncogenic K-ras. Deletion or suppression of Wt1 expression leads to senescence of primary cells expressing oncogenic K-ras under the control of the native promotor and at physiological levels, but had no effect on cells expressing wild-type K-ras. Furthermore, loss of Wt1 in lung cancer cell lines that harbor mutant K-ras leads to apoptosis. Taken together, these observations reveal a novel role for Wt1 as a key regulator of the complex genetic network required for the oncogenic effect of the small GTPase K-ras. We compare the expression profiles of K-ras mutant mouse cell line (LKR13) upon shRNA knockdown of K-ras itself or Wt1. The study provides insights into the transcriptional role of Wt1 in the context of oncogenic K-ras.
2010-03-01 | GSE15326 | GEO
Project description:K-ras is one of the most frequently mutated human oncogenes. Activation of K-ras can lead to either senescence or proliferation in primary cells. The precise mechanism governing these distinct outcomes remains unclear. Here we utilized a loss-of-function screen to assess the role of specific genes identified as potential key regulators of K-ras driven oncogenesis. Using this approach, we identify the transcription factor Wt1 as an inhibitor of senescence in primary cells expressing oncogenic K-ras. Deletion or suppression of Wt1 expression leads to senescence of primary cells expressing oncogenic K-ras under the control of the native promotor at physiological levels, but has no effect on cells expressing wild-type K-ras. Wt1 contributes to K-ras driven lung tumorigenesis in vivo and loss of Wt1 is specifically deleterious to human lung cancer cell lines that are dependent on oncogenic K-ras. Taken together, these observations reveal a novel role for Wt1 as a key regulator of the complex genetic network required for the oncogenic effect of the small GTPase K-ras. We compare the expression profiles of Wild type, K-ras mutant, Wt1-null, and double K-ras mutant/Wt1-null mouse embryonic fibroblasts (MEFs). The study provides insights into the transcriptional role of Wt1 in the context of oncogenic K-ras. MEFs were infected with adenoviral Cre to activate K-ras (6 samples), knockout Wt1 (5 samples), both activate K-ras and knockout Wt1 (7 samples). As a control, MEFs were infected with adenoviral GFP (5 samples). RNA was isolated using Trizol 7 days after infection. RNA was further prepared by passage over an RNeasy column. cDNA synthesis, biotinylation of cRNA and hybridization to mouse Genechip 430A v2 containing 39,000 probes was performed according to the manufacturer's instructions (Affymetrix, Santa Clara). Microarray data was normalized with Expression Console software (Affymetrix, Santa Clara) using RMA algorithms.
2010-03-06 | E-GEOD-15325 | biostudies-arrayexpress
Project description:Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1. Keywords: single channel
2006-10-28 | GSE6120 | GEO