Brain-Specific Rescue of Clock Reveals System-Driven Transcriptional Rhythms in Peripheral Tissue 英文参考文献.docVIP

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Brain-Specific Rescue of Clock Reveals System-Driven Transcriptional Rhythms in Peripheral Tissue 英文参考文献.doc

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Brain-Specific Rescue of Clock Reveals System-Driven Transcriptional Rhythms in Peripheral Tissue 英文参考文献

Brain-SpecificRescueofClockRevealsSystem-Driven TranscriptionalRhythmsinPeripheralTissue MichaelE.Hughes1,Hee-KyungHong2,3,JasonL.Chong2,3,4,AlejandraA.Indacochea2,SamuelS.Lee2, MichaelHan2,4,JosephS.Takahashi5,6*,JohnB.Hogenesch7* 1DepartmentofCellularandMolecularPhysiology,YaleSchoolofMedicine,NewHaven,Connecticut,UnitedStatesofAmerica,2CenterforSleepandCircadianBiology, NorthwesternUniversity,Evanston,Illinois,UnitedStatesofAmerica,3DepartmentsofNeurobiologyandPhysiology,NorthwesternUniversity,Evanston,Illinois,United StatesofAmerica,4LaboratoryofMalariaandVectorResearch,NationalInstituteofAllergyandInfectiousDiseases,NationalInstitutesofHealth,Bethesda,Maryland, UnitedStatesofAmerica,5DepartmentofNeuroscience,UniversityofTexasSouthwesternMedicalCenter,Dallas,Texas,UnitedStatesofAmerica,6HowardHughes Medical Institute,UniversityofTexasSouthwesternMedicalCenter,Dallas, Texas, UnitedStates ofAmerica, 7Department ofPharmacology,Institute for Translational MedicineandTherapeutics,UniversityofPennsylvaniaSchoolofMedicine,Philadelphia,Pennsylvania,UnitedStatesofAmerica Abstract Thecircadianregulatorynetworkisorganizedinahierarchicalfashion,withacentraloscillatorinthesuprachiasmaticnuclei (SCN)orchestratingcircadianoscillationsinperipheraltissues.Thenatureoftherelationshipbetweencentralandperipheral oscillators,however,ispoorlyunderstood.WeusedthetetOFFexpressionsystemtospecificallyrestoreClockfunctioninthe brains of ClockD19 mice, which have compromised circadian clocks. Rescued mice showed normal locomotor rhythms in constant darkness, with activity period lengths approximating wildtype controls. We used microarray analysis to assess whetherbrain-specificrescueofcircadianrhythmicitywassufficienttorestorecircadiantranscriptionaloutputintheliver. ComparedtoClockmutants,Clock-rescuemiceshowedsignificantlylargernumbersofcyclingtranscriptswithappropriate phaseandperiodlengths,includingmanycomponentsofthecorecircadianoscillator.ThisindicatesthattheSCNoscillator overco