miRNA-靶分子的檢測(cè)課件

DetectingMicroRNATargetsbyLinkingSequence,MicroRNAandGeneExpressionDataJointworkwithQuaidMorris(2)

andBrendanFrey(1),(2)JimHuang(1)ProbabilisticandStatisticalInferenceGroup,EdwardS.RogersDepartmentofElectricalandComputerEngineering,UniversityofTorontoBanting&BestDepartmentofMedicalResearch,UniversityofToronto04/02/2006RECOMB2006DetectingMicroRNATargetsby1TranscriptionalregulationTranscriptionandsplicingmRNAtranscriptProtein-codinggeneTranscriptionfactor04/02/2006RECOMB2006TranscriptionalregulationTran2Post-transcriptionalregulationMaturemicroRNAmicroRNAtargetsiteRISCmRNAtranscriptSilencingmicroRNAgene04/02/2006RECOMB2006Post-transcriptionalregulatio3miRNA-靶分子的檢測(cè)課件4miRNA-靶分子的檢測(cè)課件5MechanismsformicroRNAregulationTorontomicroRNA,mRNAandproteindataTargetScanSmicroRNAtargetpredictionsRISCTranscriptionTranscriptionTranslationRISCmiRNAxyzmRNAproteinxyzmiRNAmRNAproteinPost-transcriptionaldegradationTranslationalrepressionCombine:04/02/2006RECOMB2006MechanismsformicroRNAregula61,770TargetScanScandidatetargetslinking788targetedmRNAtranscriptsto22microRNAsin17tissuesLinkingmicroRNAandmRNAexpressionmiR-16/SpleenExpressionofputativetargetsBackgroundexpressionp<10-704/02/2006RECOMB20061,770TargetScanScandidateta7GenMiRGenerativemodelformicroRNAregulationGetcandidatetargetsmicroRNAsequencedatamRNAsequencedatamicroRNAexpressiondatamRNAexpressiondataDetectedmicroRNAtargetsGCATCATAACTGCA…04/02/2006RECOMB2006GenMiRGenerativemodelformic8Observed:SetofcandidatemicroRNAtargetsmicroRNAexpressiondatamRNAexpressiondataUnobserved:IndicatorvariablesModelparameters:RegulatoryweightforeachmicroRNABackgroundlevelofmRNAexpressionTheGenMiRmethod04/02/2006RECOMB2006Observed:TheGenMiRmethod04/09SomenotationmessengerRNAmicroRNAIndicatorvariableforwhethermicroRNAktrulytargetsmRNAgregulatoryweightIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptg04/02/2006RECOMB2006SomenotationmessengerRNAmicro10ABayesiannetworkfordetectingmicroRNAtargets

IndicatorvariableforwhethermicroRNAktrulytargetstranscriptgmicroRNAexpressionlevelTargettranscriptexpressionlevelIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptgxgtzktsgkcgktissuest=1,…,TmicroRNAsk=1,…,KmessengerRNAsg=1,…,G04/02/2006RECOMB2006ABayesiannetworkfordetecti11AprobabilisticmodelformicroRNAregulationIndicatorvariableforwhethermicroRNAktrulytargetstranscriptgmicroRNAexpressionlevelTargettranscriptexpressionlevelIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptgxgtzktsgkcgktissuest=1,…,TmicroRNAsk=1,…,KmessengerRNAsg=1,…,G04/02/2006RECOMB2006Aprobabilisticmodelformicr12AprobabilisticmodelformicroRNAregulationTargetingprobabilitiesIndicatorvariableforwhethermicroRNAktrulytargetstranscriptgIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptgsgkcgk04/02/2006RECOMB2006Aprobabilisticmodelformicr13AprobabilisticmodelformicroRNAregulationIndicatorvariableforwhethermicroRNAktrulytargetstranscriptgmicroRNAexpressionlevelTargettranscriptexpressionlevelIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptgxgtzktsgkcgktissuest=1,…,TmicroRNAsk=1,…,KmessengerRNAsg=1,…,G04/02/2006RECOMB2006Aprobabilisticmodelformicr14AprobabilisticmodelformicroRNAregulationProbabilityofdatagiventargetinginteractionIndicatorvariableforwhethermicroRNAktrulytargetstranscriptgmicroRNAexpressionlevelTargettranscriptexpressionlevelxgtzktsgk04/02/2006RECOMB2006Aprobabilisticmodelformicr15AprobabilisticmodelformicroRNAregulationTargetingprobabilitiesProbabilityofdatagiventargetinginteractionJointprobability04/02/2006RECOMB2006Aprobabilisticmodelformicr16Maximizelikelihoodofobserveddata:Upperboundonnegativeloglikelihood:LearningmicroRNAtargetsGOAL:OptimizefitofmodeltodataInferenceParameterestimationOR04/02/2006RECOMB2006Maximizelikelihoodofobserve17Exactinference:Posteriorisintractabletocompute!Approximatetheposteriordistribution:VariationalInference04/02/2006RECOMB2006Exactinference:VariationalIn18DetectingmicroRNAtargetsPermutedmiRNAdatamiRNAdata04/02/2006RECOMB2006DetectingmicroRNAtargetsPerm19DetectingmicroRNAtargetsLESSONS:1)WeCANlearnfromexpressionandsequencedata!2)Combinatoricsarecriticalforlearningtargets!04/02/2006RECOMB2006DetectingmicroRNAtargetsLESS20SummaryEvidencethatmicroRNAsoperatebydegradingtargetmRNAsModelforcombinatorialmicroRNAregulationHigh-throughputmethodforlearningbonafidemiRNAtargetsFulllistofdetectedmicroRNAtargetsisavailableat/~GenMiR/

04/02/2006RECOMB2006SummaryEvidencethatmicroRNAs21Theroadahead…J.C.Huang,Q.D.MorrisandB.J.Frey.BayesianLearningofMicroRNATargetsfromSequenceandExpressionData(submittedforpublication)DifferencesinnormalizationandhybridizationconditionsinmRNAandmicroRNAdata?BayesianlearningRobustnessofmodelandlearningalgorithmtoSubsamplingofdata?Introducingfaketargets?Biologicalverificationandnetworkmining

04/02/2006RECOMB2006Theroadahead…J.C.Huang,Q.D22Sufficientstatistics04/02/2006RECOMB2006Sufficientstatistics04/02/20023VariationalExpectation-MaximizationVariationalE-stepVariationalM-stepGOAL:Optimizefitofmodeltodataandlookatgk’s04/02/2006RECOMB2006VariationalExpectation-Maximi24VariationalEMupdatesVariationalE-stepVariationalM-step04/02/2006RECOMB2006VariationalEMupdatesVariatio25CombinatorialmicroRNAregulation04/02/2006RECOMB2006CombinatorialmicroRNAregulat26RobustnessoftheGenMiRmodel04/02/2006RECOMB2006RobustnessoftheGenMiRmodel27DetectingMicroRNATargetsbyLinkingSequence,MicroRNAandGeneExpressionDataJointworkwithQuaidMorris(2)

andBrendanFrey(1),(2)JimHuang(1)ProbabilisticandStatisticalInferenceGroup,EdwardS.RogersDepartmentofElectricalandComputerEngineering,UniversityofTorontoBanting&BestDepartmentofMedicalResearch,UniversityofToronto04/02/2006RECOMB2006DetectingMicroRNATargetsby28TranscriptionalregulationTranscriptionandsplicingmRNAtranscriptProtein-codinggeneTranscriptionfactor04/02/2006RECOMB2006TranscriptionalregulationTran29Post-transcriptionalregulationMaturemicroRNAmicroRNAtargetsiteRISCmRNAtranscriptSilencingmicroRNAgene04/02/2006RECOMB2006Post-transcriptionalregulatio30miRNA-靶分子的檢測(cè)課件31miRNA-靶分子的檢測(cè)課件32MechanismsformicroRNAregulationTorontomicroRNA,mRNAandproteindataTargetScanSmicroRNAtargetpredictionsRISCTranscriptionTranscriptionTranslationRISCmiRNAxyzmRNAproteinxyzmiRNAmRNAproteinPost-transcriptionaldegradationTranslationalrepressionCombine:04/02/2006RECOMB2006MechanismsformicroRNAregula331,770TargetScanScandidatetargetslinking788targetedmRNAtranscriptsto22microRNAsin17tissuesLinkingmicroRNAandmRNAexpressionmiR-16/SpleenExpressionofputativetargetsBackgroundexpressionp<10-704/02/2006RECOMB20061,770TargetScanScandidateta34GenMiRGenerativemodelformicroRNAregulationGetcandidatetargetsmicroRNAsequencedatamRNAsequencedatamicroRNAexpressiondatamRNAexpressiondataDetectedmicroRNAtargetsGCATCATAACTGCA…04/02/2006RECOMB2006GenMiRGenerativemodelformic35Observed:SetofcandidatemicroRNAtargetsmicroRNAexpressiondatamRNAexpressiondataUnobserved:IndicatorvariablesModelparameters:RegulatoryweightforeachmicroRNABackgroundlevelofmRNAexpressionTheGenMiRmethod04/02/2006RECOMB2006Observed:TheGenMiRmethod04/036SomenotationmessengerRNAmicroRNAIndicatorvariableforwhethermicroRNAktrulytargetsmRNAgregulatoryweightIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptg04/02/2006RECOMB2006SomenotationmessengerRNAmicro37ABayesiannetworkfordetectingmicroRNAtargets

IndicatorvariableforwhethermicroRNAktrulytargetstranscriptgmicroRNAexpressionlevelTargettranscriptexpressionlevelIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptgxgtzktsgkcgktissuest=1,…,TmicroRNAsk=1,…,KmessengerRNAsg=1,…,G04/02/2006RECOMB2006ABayesiannetworkfordetecti38AprobabilisticmodelformicroRNAregulationIndicatorvariableforwhethermicroRNAktrulytargetstranscriptgmicroRNAexpressionlevelTargettranscriptexpressionlevelIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptgxgtzktsgkcgktissuest=1,…,TmicroRNAsk=1,…,KmessengerRNAsg=1,…,G04/02/2006RECOMB2006Aprobabilisticmodelformicr39AprobabilisticmodelformicroRNAregulationTargetingprobabilitiesIndicatorvariableforwhethermicroRNAktrulytargetstranscriptgIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptgsgkcgk04/02/2006RECOMB2006Aprobabilisticmodelformicr40AprobabilisticmodelformicroRNAregulationIndicatorvariableforwhethermicroRNAktrulytargetstranscriptgmicroRNAexpressionlevelTargettranscriptexpressionlevelIndicatorofputativeinteractionbetweenmicroRNAkandtargettranscriptgxgtzktsgkcgktissuest=1,…,TmicroRNAsk=1,…,KmessengerRNAsg=1,…,G04/02/2006RECOMB2006Aprobabilisticmodelformicr41AprobabilisticmodelformicroRNAregulationProbabilityofdatagiventargetinginteractionIndicatorvariableforwhethermicroRNAktrulytargetstranscriptgmicroRNAexpressionlevelTargettranscriptexpressionlevelxgtzktsgk04/02/2006RECOMB2006Aprobabilisticmodelformicr42AprobabilisticmodelformicroRNAregulationTargetingprobabilitiesProbabilityofdatagiventargetinginteractionJointprobability04/02/2006RECOMB2006Aprobabilisticmodelformicr43Maximizelikelihoodofobserveddata:Upperboundonnegativeloglikelihood:LearningmicroRNAtargetsGOAL:OptimizefitofmodeltodataInferenceParameterestimationOR04/02/2006RECOMB2006Maximizelikelihoodofobserve44Exactinference:Posteriorisintractabletocompute!Approximatetheposteriordistribution:VariationalInference04/02/2006RECOMB2006Exactinference:VariationalIn45DetectingmicroRNAtargetsPermutedmiRNAdatamiRNAdata04/02/2006RECOMB2006DetectingmicroRNAtargetsPerm46DetectingmicroRNAtargetsLESSONS:1)WeCANlearnfromexpressionandsequencedata!2)Combinatoricsarecriticalforlearningtargets!04/02/2006RECOMB2006DetectingmicroRNAtargetsLESS47SummaryEvidencethatmicroRNAsoperatebydegradingtar