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The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

ABSTRACT: The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

PROVIDER: PRJNA641358 | ENA |

REPOSITORIES: ENA

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The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

Project description:Wilms tumour (WT), a childhood kidney cancer with embryonal origins, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of fetal kidney with two WT cell lines, using methyl-CpG immunoprecipitation. We filtered our results to remove common cancer-associated epigenetic changes, and to enrich for genes involved in early kidney development. This identified four candidate genes that were hypermethylated in WT cell lines compared to fetal kidney, of which ESRP2 (epithelial splicing regulatory protein 2), was the most promising gene for further study. ESRP2 was commonly repressed by DNA methylation early in WT development (in nephrogenic rests) and could be reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was expressed in WT cell lines, it acted as an inhibitor of cellular proliferation in vitro and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA-seq of the ESRP2-expressing WT cell lines identified several novel splicing targets, in addition to well-characterised targets of ESRP2. One of these targets, LEF1, is a component of the Wnt signalling pathway that is essential for kidney development and commonly disrupted in WT. We propose a model in which the Wnt pathway can be disrupted in early kidney development to generate WT, either by genetic abnormalities such as WT1 mutations, or by epigenetic defects, such as ESRP2 methylation. The microarray data in this deposition identified ESRP2 as a commonly hypermethylated gene in Wilms tumour.

2020-11-02 | GSE153047 | GEO

The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumor and acts as a tumor suppressor

Project description:Wilms tumor (WT), a childhood kidney cancer with embryonal origins, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of fetal kidney with two WT cell lines, using methyl-CpG immunoprecipitation. We filtered our results to remove common cancer-associated epigenetic changes, and to enrich for genes involved in early kidney development. This identified four candidate genes that were hypermethylated in WT cell lines compared to fetal kidney, of which ESRP2 (epithelial splicing regulatory protein 2), was the most promising gene for further study. ESRP2 was commonly repressed by DNA methylation early in WT development (in nephrogenic rests) and could be reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was expressed in WT cell lines, it acted as an inhibitor of cellular proliferation in vitro and in vivo it suppressed tumor growth of orthotopic xenografts in nude mice. RNA-seq of the ESRP2-expressing WT cell lines identified several novel splicing targets, in addition to well-characterised targets of ESRP2. One of these targets, LEF1, is a component of the Wnt signalling pathway that is essential for kidney development and commonly disrupted in WT. We propose a model in which the Wnt pathway can be disrupted in early kidney development to generate WT, either by genetic abnormalities such as WT1 mutations, or by epigenetic defects, such as ESRP2 methylation.

2020-11-02 | GSE154496 | GEO

The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumor and acts as a tumor suppressor

Project description:The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumor and acts as a tumor suppressor

| PRJNA646492 | ENA

Genome-wide analysis of DNA methylation in neuroblastoma cell lines identifies MEGF10 as a novel epigenetically repressed tumour suppressor gene.

Project description:Background: Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome-wide mutation analyses, most neuroblastomas do not contain recognisable driver mutations, suggesting that epigenetic changes could underlie many cases. Methods: To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we compared neuroblastomas to their neural crest precursor cells, using genome-wide DNA methylation analysis; probing CpG island promoter microarrays with methyl CpG-immunoprecipitated DNA. Results: We identified 93 genes that were significantly differently methylated between neuroblastoma cell lines and neural crest cells, of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumour suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down-regulated expression in neuroblastoma tumour samples; furthermore patients with the lowest-expressing tumours had reduced relapse-free survival. Knock-down of MEGF10 expression in neuroblastoma cell lines promoted cell growth. Conclusion: Our results suggest that MEGF10 is a clinically relevant, epigenetically-deregulated neuroblastoma tumour suppressor.

2016-11-30 | GSE71958 | GEO

The Wilms' tumour 1 transcription factor regulates epigenetic states via DNA methyltransferase 3A

Project description:The Wilms' tumour 1 transcription factor regulates epigenetic states via DNA methyltransferase 3A.

2012-11-05 | GSE39713 | GEO

Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour

Project description:Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour

2009-02-27 | GSE15027 | GEO

Characterizing MYCN targets in Wilms' tumour

Project description:Transcriptomic analysis of MYCN targets in anaplastic Wilms' tumour cells

| PRJEB41686 | ENA

MicroRNA profiling of Wilms Tumour 1 deleted and induced embryonic stem cells

Project description:We report the microRNA profiles of the mouse embryonic stem cell (E14IV), which have been deleted for tumour suppressor Wilms' Tumour 1 (WT1), and induced with retinoic acid. Additionally, cells that had an inducibe WT1 expression where also used to compare the microRNA profile during different time points of WT1 induction.

2024-03-26 | GSE169684 | GEO

Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour

Project description:Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour The data consists of five microarrays hybridized with methylated DNA immunoprecipitated from Wilms' tumours and from a normal foetal kidney control

2010-05-22 | E-GEOD-15027 | biostudies-arrayexpress

The developmental programme for genesis of the entire kidney is recapitulated in Wilms tumour

Project description:Expression profiling of Wilms tumour samples, which identified molecular signatures of the ureteric bud and collecting duct as well as those of the proximal and distal tubules in triphasic histology tumours. These observations indicate Wilms tumours can arise from a precursor cell capable of generating the entire kidney, such as the cells of the intermediate mesoderm from which both the metanephric mesenchym and ureteric bud are derived.

2017-12-31 | E-MTAB-3516 | biostudies-arrayexpress

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