A Machine Learning Approach for Identifying Novel Cell Type–Specific Transcriptional Regulators of Myogenesis 英文参考文献.docVIP

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A Machine Learning Approach for Identifying Novel Cell Type–Specific Transcriptional Regulators of Myogenesis 英文参考文献.doc

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A Machine Learning Approach for Identifying Novel Cell Type–Specific Transcriptional Regulators of Myogenesis 英文参考文献

AMachineLearningApproachforIdentifyingNovelCell Type–SpecificTranscriptionalRegulatorsofMyogenesis BrianW.Busser1.,LeilaTaher2.,YongsokKim1,TereseTansey1,MollyJ.Bloom1,IvanOvcharenko2*, AlanM.Michelson1* 1LaboratoryofDevelopmentalSystemsBiology,NationalHeart,Lung,andBloodInstitute,NationalInstitutesofHealth,Bethesda,Maryland,UnitedStatesofAmerica, 2ComputationalBiologyBranch,NationalCenterforBiotechnologyInformation,NationalLibraryofMedicine,NationalInstitutesofHealth,Bethesda,Maryland,United StatesofAmerica Abstract Transcriptionalenhancersintegratethecontributionsofmultipleclassesoftranscriptionfactors(TFs)toorchestratethemyriad spatio-temporalgeneexpressionprogramsthatoccurduringdevelopment.Amolecularunderstandingofenhancerswith similaractivitiesrequirestheidentificationofboththeiruniqueandtheirsharedsequencefeatures.Toaddressthisproblem, wecombinedphylogeneticprofilingwithaDNA–basedenhancersequenceclassifierthatanalyzestheTFbindingsites(TFBSs) governingthetranscriptionofaco-expressedgeneset.Wefirstassembledasmallnumberofenhancersthatareactivein Drosophila melanogaster muscle founder cells (FCs) and other mesodermal cell types. Using phylogenetic profiling, we increasedthenumberofenhancersbyincorporatingorthologousbutdivergentsequencesfromotherDrosophilaspecies. FunctionalassaysrevealedthatthedivergedenhancerorthologswereactiveinlargelysimilarpatternsastheirD.melanogaster counterparts,althoughtherewasextensiveevolutionaryshufflingofknownTFBSs.Wethenbuiltandtrainedaclassifierusing thisenhancersetandidentifiedadditionalrelatedenhancersbasedonthepresenceorabsenceofknownandputativeTFBSs. Predicted FC enhancers were over-represented in proximity to known FC genes; and many of the TFBSs learned by the classifierwerefoundtobecriticalforenhanceractivity,includingPOUhomeodomain,Myb,Ets,Forkhead,andT-boxmotifs. EmpiricaltestingalsorevealedthattheT-boxTFencodedbyorg-1isapreviouslyuncharacterizedregulatorofmusclecell identity.Finally,wefoundextensivediversityinthecompositi