Egr-1 Induces a Profibrotic InjuryRepair Gene Program Associated with Systemic Sclerosis 英文参考文献.docVIP

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Egr-1 Induces a Profibrotic InjuryRepair Gene Program Associated with Systemic Sclerosis 英文参考文献.doc

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Egr-1 Induces a Profibrotic InjuryRepair Gene Program Associated with Systemic Sclerosis 英文参考文献

Egr-1InducesaProfibroticInjury/RepairGeneProgram AssociatedwithSystemicSclerosis SwatiBhattacharyya1*,JenniferL.Sargent2,PanDu3,SimonLin3,WarrenG.Tourtellotte4 ,Kazuhiko Takehara5,MichaelL.Whitfield2,JohnVarga1* 1Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America, 2Department of Genetics, Dartmouth MedicalSchool,Hanover,NewHampshire,UnitedStatesofAmerica,3NorthwesternUniversityClinicalandTranslationalSciencesInstitute,Chicago,Illinois,UnitedStates ofAmerica,4DepartmentsofPathologyandNeurology,FeinbergSchoolofMedicine,NorthwesternUniversity,Chicago,Illinois,UnitedStatesofAmerica,5Department ofDermatology,KanazawaUniversity,Kanazawa,Japan Abstract Transforming growth factor-? (TGF-?) signaling is implicated in the pathogenesis of fibrosis in scleroderma or systemic sclerosis (SSc), but the precise mechanisms are poorly understood. The immediate-early gene Egr-1 is an inducible transcription factor with key roles in mediating fibrotic TGF-? responses. To elucidate Egr-1 function in SSc-associated fibrosis,weexaminedchangeingeneexpressioninducedbyEgr-1inhumanfibroblastsatthegenome-widelevel.Using microarray expression analysis, we derived a fibroblast ‘‘Egr-1-responsive gene signature’’ comprising over 600 genes involvedincellproliferation,TGF-?signaling,woundhealing,extracellularmatrixsynthesisandvasculardevelopment.The experimentally derived ‘‘Egr-1-responsive gene signature’’ was then evaluated in an expression microarray dataset comprisingskinbiopsiesfrom27patientswithlocalizedandsystemicformsofsclerodermaandsixhealthycontrols.We foundthatthe‘‘Egr-1responsivegenesignature’’wassubstantiallyenrichedinthe‘‘diffuse-proliferation’’subsetcomprising exclusively of patients with diffuse cutaneous SSc (dcSSc) of skin biopsies. A number of Egr-1-regulated genes was also associatedwiththe‘‘inflammatory’’intrinsicsubset.OnlyaminorityofEgr-1-regulatedgeneswasconcordantlyregulatedby TGF-?.Theseresultsindic