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| Status |
Public on Nov 02, 2020 |
| Title |
The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by array
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| Summary |
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.
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| Overall design |
Genome-wide DNA methylation was compared between fetal kidney (commercial; Biochain) and two Wilms tumour cell lines (17.94; Brown et al (2012) Cancer Genet 205:319-26 and Wit49; Alami et al (2003) Int J Cancer 107:365-74). The methylated fraction from each genomic DNA was purified by MCIP (see extract protocol) and co-hybridised with total genomic DNA onto a custom Nimblegen microarray. There was a single array used for each sample.
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| Contributor(s) |
Szemes M, Malik KT, Brown KW |
| Citation(s) |
34520622 |
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| Submission date |
Jun 23, 2020 |
| Last update date |
Sep 30, 2021 |
| Contact name |
Keith William Brown |
| E-mail(s) |
[email protected]
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| Phone |
+441173312071
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| Organization name |
University of Bristol
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| Department |
School of Cellular and Molecular Medicine
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| Lab |
Cancer Epigenetics Laboratory
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| Street address |
Biomedical Sciences Building, University Walk
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| City |
Bristol |
| State/province |
- |
| ZIP/Postal code |
BS8 1TD |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL28758 |
NimbleGen 007-01-30_HG18_5189_refseq |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA641358 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE153047_RAW.tar |
79.1 Mb |
(http)(custom) |
TAR (of GFF, PAIR) |
| Processed data provided as supplementary file |
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