Module Network Inference from a Cancer Gene Expression Data Set Identifies MicroRNA Regulated Modules 英文参考文献.docVIP

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Module Network Inference from a Cancer Gene Expression Data Set Identifies MicroRNA Regulated Modules 英文参考文献.doc

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Module Network Inference from a Cancer Gene Expression Data Set Identifies MicroRNA Regulated Modules 英文参考文献

ModuleNetworkInferencefromaCancerGene ExpressionDataSetIdentifiesMicroRNARegulated Modules EricBonnet1,2,MarianthiTatari3,4,AnaghaJoshi1,2,TomMichoel1,2,KathleenMarchal5,GeertBerx3,4, YvesVandePeer1,2 * 1Department of Plant Systems Biology, VIB, Gent, Belgium, 2Department of Molecular Genetics, Ghent University, Gent, Belgium, 3Unit of Molecular and Cellular Oncology,DepartmentforMolecularBiomedicalResearch,VIB,Gent,Belgium,4DepartmentofBiomedicalMolecularBiology,GhentUniversity,Gent,Belgium,5CMPG, DepartmentMicrobialandMolecularSystems,KULeuven,Leuven,Belgium Abstract Background: MicroRNAs (miRNAs) are small RNAs that recognize and regulate mRNA target genes. Multiple lines of evidenceindicatethattheyarekeyregulatorsofnumerouscriticalfunctionsindevelopmentanddisease,includingcancer. However, defining the place and function of miRNAs in complex regulatory networks is not straightforward. Systems approaches,liketheinferenceofamodulenetworkfromexpressiondata,canhelptoachievethisgoal. Methodology/PrincipalFindings:Duringthelastdecade,muchprogresshasbeenmadeinthedevelopmentofrobustand powerful module network inference algorithms. In this study, we analyze and assess experimentally a module network inferredfrombothmiRNAandmRNAexpressiondata,usingourrecentlydevelopedmodulenetworkinferencealgorithm based on probabilistic optimization techniques. We show that several miRNAs are predicted as statistically significant regulatorsforvariousmodulesoftightlyco-expressedgenes.Adetailedanalysisofthreeofthosemodulesdemonstrates thatthespecificassignmentofmiRNAsisfunctionallycoherentandsupportedbyliterature.Wefurtherdesignedasetof experimentstotesttheassignmentofmiR-200aasthetopregulatorofasmallmoduleofninegenes.Theresultsstrongly suggestthatmiR-200aisregulatingthemodulegenesviathetranscriptionfactorZEB1.Interestingly,thismoduleismost likelyinvolvedinepithelialhomeostasisanditsdysregulationmightcontributetothemalignantprocessincancercells. Conclusions/Significance: Ourresultsshowth