Downregulation of WT1 transcription factor gene expression is required to promote myocardial fate
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ABSTRACT:
PROVIDER: PRJNA744138 | ENA |
REPOSITORIES: ENA
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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: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:Downregulation of WT1 transcription factor gene expression is required to promote myocardial fate [RNA-seq]
| PRJNA744141 | ENA
Project description:Downregulation of WT1 transcription factor gene expression is required to promote myocardial fate [ATAC-seq]
| PRJNA744144 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-03-08 | GSE179522 | GEO
Project description:The Wilms´ tumor 1 gene (WT1) encodes a transcription factor involved in cell growth and development. As we previously reported WT1 expression is hardly detectable in normal hepatic tissue but is induced in liver cirrhosis. Although WT1 has been found to be overexpressed in a number of malignancies, the role of WT1 in hepatocarcinogenesis has not been clarified. We found that WT1 is expressed in several human hepatocellular carcinoma (HCC) cell lines including PLC/PRF/5 and HepG2, and in HCC tumor tissue in 42% of patients. WT1 small interfering RNAs did not affect proliferation rate of HCC cells but abrogated their resistance to anoikis. Transcriptome analysis of PLC/PRF/5 cells after WT1 knockdown demonstrated upregulation of 251 genes and downregulation of 321. Ninety per cent of the former corresponded to metabolic genes mostly those characterizing the mature hepatocyte phenotype. On the contrary, genes that decreased upon WT1 inhibition were mainly related to defense against apoptosis, cell cycle and tumor progression. In agreement with these findings WT1 expression increased the resistance of liver tumor cells to doxorubicin, a compound used to treat HCC. Interestingly, doxorubicin strongly enhanced WT1 expression in both HCC cells and normal human hepatocytes. Among different chemotherapeutics, induction of WT1 transcription was restricted to topoisomerase 2 inhibitors. When WT1 expression was prohibited doxorubicin caused a marked increase in caspase-3 activation. In conclusion, WT1 is expressed in a substantial proportion of HCC contributing to tumor progression and resistance to chemotherapy, suggesting that WT1 may be an important target for HCC treatment. Keywords: Cell type comparison
2008-10-03 | GSE12886 | GEO
Project description:Interventions: A patient is vaccinated with Montanide ISA51-adjuvanted WT1 Trio cancer vaccine consisting of two WT1 CTL peptides (WT1-126 and WT1-235) and one WT1 HTL peptide (WT1-332) (2mg each) seven times at the interval of two weeks.
Primary outcome(s): Induction of WT1-specific immune responses assessed by WT1-related tests such as WT1-DTH skin reaction and serum levels of WT1 peptide IgG autoantibody at 1M, 2M, and 3M of WT1 Trio vaccine.
Study Design: Single arm Non-randomized
| 2638832 | ecrin-mdr-crc
Project description:Interventions: A patient is vaccinated with Montanide ISA51-adjuvanted WT1 Trio cancer vaccine consisting of two WT1 CTL peptides (WT1-126 and WT1-235) and one WT1 HTL peptide (WT1-332) (2mg each) seven times at the interval of two to four weeks. The interval can be changed within a range from one to 16 weeks.
Primary outcome(s): Induction of WT1-specific immune responses assessed by WT1-related tests such as WT1-DTH skin reaction, serum levels of WT1 peptide IgG autoantibody, and frequency of WT1-CTL in PB * This is evaluated at the interval ranging from 6 to 12 months.
Study Design: Single arm Non-randomized
| 2638831 | ecrin-mdr-crc
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: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