A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology 英文参考文献.docVIP

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A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology 英文参考文献.doc

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A Novel HMM-Based Method for Detecting Enriched Transcription Factor Binding Sites Reveals RUNX3 as a Potential Target in Pancreatic Cancer Biology 英文参考文献

ANovelHMM-BasedMethodforDetectingEnriched TranscriptionFactorBindingSitesRevealsRUNX3asa PotentialTargetinPancreaticCancerBiology LironLevkovitz1,2,NirYosef2,MarvinC.Gershengorn3,EytanRuppin1,2,RodedSharan2*. ,Yoram Oron1*. 1DepartmentofPhysiologyandPharmacology,SacklerFacultyofMedicine,TelAvivUniversity,TelAviv,Israel,2SchoolofComputerScience,TelAvivUniversity,TelAviv, Israel,3ClinicalEndocrinologyBranch,NationalInstituteofDiabetesandDigestiveandKidneyDiseases,NationalInstitutesofHealth,Bethesda,Maryland,UnitedStatesof America Abstract Background:Pancreaticadenocarcinoma(PAC)isoneofthemostintractablemalignancies.Inordertosearchforpotential newtherapeutictargets,wereliedoncomputationalmethodsaimedatidentifyingtranscriptionfactorbindingsites(TFBSs) over-representedinthepromoterregionsofgenesdifferentiallyexpressedinPAC.Thoughmanycomputationalmethods havebeenimplementedtoaccomplishthis,nonehasgainedoverallacceptanceorproducedprovennoveltargetsinPAC. TothisendwehavedevelopedDEMON,anovelmethodformotifdetection. Methodology:DEMONreliesonahiddenMarkovmodeltoscoretheappearanceofsequencemotifs,takingintoaccountall potentialsitesinapromoterofpotentiallyvaryingbindingaffinities.WedemonstrateDEMON’saccuracyonsimulatedand realdatasets.ApplyingDEMONtoPAC-relateddatasetsidentifiestheRUNXfamilyashighlyenrichedinPAC-relatedgenes. UsinganovelexperimentalparadigmtodistinguishbetweennormalandPACcells,wefindthatRUNX3mRNA(butnot RUNX1 or RUNX2 mRNAs) exhibits time-dependent increases in normal but not in PAC cells. These increases are accompaniedbychangesinmRNAlevelsofputativeRUNXgenetargets. Conclusions:TheintegratedapplicationofDEMONandanoveldifferentiationsystemledtotheidentificationofasingle family member, RUNX3, which together with four of its putative targets showed a robust response to a differentiation stimulusinhealthycells,whereasthisregulatorymechanismwasabsentinPACcells,emphasizingRUNX3asapromising targetforfurtherstudies. Citation: Levkovitz L, Yosef N, Gershengorn MC, Rupp