egr-1 induces a profibrotic injuryrepair gene program associated with systemic sclerosisegr-1诱发一个profibrotic injuryrepair基因程序与系统性硬化有关.pdfVIP

Egr-1 Induces a Profibrotic Injury/Repair Gene Program Associated with Systemic Sclerosis 1 2 3 3 4 Swati Bhattacharyya *, Jennifer L. Sargent , Pan Du , Simon Lin , Warren G. Tourtellotte , Kazuhiko 5 2 1 Takehara , Michael L. Whitfield , John Varga * 1 Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America, 2 Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire, United States of America, 3 Northwestern University Clinical and Translational Sciences Institute, Chicago, Illinois, United States of America, 4 Departments of Pathology and Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America, 5 Department of Dermatology, Kanazawa University, Kanazawa, Japan Abstract Transforming growth factor-ß (TGF-ß) 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-ß responses. To elucidate Egr-1 function in SSc-associated fibrosis, we examined change in gene expression induced by Egr-1 in human fibroblasts at the genome-wide level. Using microarray expression analysis, we derived a fibroblast ‘‘Egr-1-responsive gene signature’’ comprising over 600 genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. The experimentally derived ‘‘Egr-1-responsive gene signature’’ was then evaluated