Pluto Bioinformatics

GSE154496: The epithelial splicingregulatorESRP2is epigenetically repressed by DNA hypermethylation in Wilms tumorand acts as a tumor suppressor

Bulk RNA sequencing

Wilms tumor(WT), a childhood kidney cancer with embryonal origins, has been extensively characterised forgenetic andepigeneticalterations, but aproportion ofWTs still lack identifiableabnormalities. To uncoverDNA methylationchanges critical for WTpathogenesis, we compared the epigenome offetalkidneywithtwo WTcell lines, using methyl-CpG immunoprecipitation.We filtered ourresultsto remove common cancer-associatedepigenetic changes, and to enrich for genes involved in early kidney development. This identified four candidate genes that werehypermethylatedin WTcell lines compared tofetalkidney, of whichESRP2(epithelial splicing regulatory protein 2),wasthe most promising genefor further study.ESRP2was commonly repressedby DNA methylationearly in WT development (in nephrogenic rests)andcouldbe reactivated by DNA methyltransferase inhibition in WTcell lines.WhenESRP2was expressedin WTcell lines,it acted as an inhibitor of cellular proliferationin vitroandin vivoitsuppressed tumor growth of orthotopic xenografts in nude mice.RNA-seqof the ESRP2-expressingWTcell lines identifiedseveral novel splicing targets, in addition to well-characterised targets of ESRP2.One of these targets,LEF1, is a component of theWntsignallingpathway that is essential for kidneydevelopmentand commonly disrupted in WT.We propose a model in which theWntpathwaycan be disrupted in earlykidneydevelopmentto generate WT, either by genetic abnormalitiessuchasWT1mutations, or byepigeneticdefects, such asESRP2methylation. SOURCE: Keith,William,Brown (keith.brown@bristol.ac.uk) - Cancer Epigenetics Laboratory University of Bristol

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