title: Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis.
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 in an expression microarray dataset comprising skin biopsies from 27 patients with localized and systemic forms of scleroderma and six healthy controls. We found that the "Egr-1 responsive gene signature" was substantially enriched in the "diffuse-proliferation" subset comprising exclusively of patients with diffuse cutaneous SSc (dcSSc) of skin biopsies. A number of Egr-1-regulated genes was also associated with the "inflammatory" intrinsic subset. Only a minority of Egr-1-regulated genes was concordantly regulated by TGF-ß. These results indicate that Egr-1 induces a distinct profibrotic/wound healing gene expression program in fibroblasts that is associated with skin biopsies from SSc patients with diffuse cutaneous disease. These observations suggest that targeting Egr-1 expression or activity might be a novel therapeutic strategy to control fibrosis in specific SSc subsets.
authors.affiliation: Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America. s-bhattacharyya@northwestern.edu
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sargent
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.forename: Simon
authors.initials: S
authors.lastname: Lin
authors.forename: Warren G
authors.initials: WG
authors.lastname: Tourtellotte
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D023281:Genomics; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D012867:Skin / Q000473:pathology; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D016212:Transforming Growth Factor beta