Diversity and Plasticity of Th Cell Types Predicted from Regulatory Network Modelling 英文参考文献.docVIP

DiversityandPlasticityofThCellTypesPredictedfrom RegulatoryNetworkModelling Aure′lienNaldi1,2,JorgeCarneiro3,ClaudineChaouiya1,3,DenisThieffry1,4,5 * 1TechnologicalAdvancesforGenomicsandClinics,INSERMU928,Marseille,France,2CenterforIntegrativeGenomics,UniversityofLausanne,Lausanne,Switzerland, 3InstitutoGulbenkiandeCie?ncia,Oeiras,Portugal,4CONTRAINTESProject,INRIAParis-Rocquencourt,Rocquencourt,France,5InstitutedeBiologiedel’EcoleNormale Supe′rieure,CNRS8197,INSERM1024,Paris,France Abstract Alternative cell differentiation pathways are believed to arise from the concerted action of signalling pathways and transcriptionalregulatorynetworks.However,thepredictionofmammaliancelldifferentiationfromtheknowledgeofthe presence of specific signals and transcriptional factors is still a daunting challenge. In this respect, the vertebrate hematopoieticsystem,withitsmanybranchingdifferentiationpathwaysandcelltypes,isacompellingcasestudy.Inthis paper,weproposeanintegrated,comprehensivemodeloftheregulatorynetworkandsignallingpathwayscontrollingTh celldifferentiation.Asmostavailabledataarequalitative,werelyonalogicalformalismtoperformextensivedynamical analyses. To cope with the size and complexity of the resulting network, we use an original model reduction approach together with a stable state identification algorithm. To assess the effects of heterogeneous environments on Th cell differentiation, we have performed a systematic series of simulations considering various prototypic environments. Consequently, we haveidentified stable states corresponding to canonical Th1, Th2, Th17 and Treg subtypes, but these were found to coexist with other transient hybrid cell types that co-express combinations of Th1, Th2, Treg and Th17 markersinanenvironment-dependentfashion.Intheprocess,ourlogicalanalysishighlightsthenatureofthesecelltypes andtheirrelationshipswithcanonicalThsubtypes.Finally,ourlogicalmodelcanbeusedtoexplorenoveldifferentiation pathwaysinsilico. Citation:NaldiA,CarneiroJ,C