title: Epigenetic suppression of Fli1, a potential predisposing factor in the pathogenesis of systemic sclerosis.
abstract: Systemic sclerosis (SSc) is a multisystem connective tissue disease featured by immune abnormalities, vasculopathy and tissue fibrosis with unknown etiology. A series of studies on disease-susceptibility genes and twins have demonstrated the association of genetic factors with autoimmunity and disease severity and the contribution of environmental factors to the induction of clinical features in this disease. Friend leukemia virus integration 1 (Fli1), a member of Ets transcription factor family, is epigenetically suppressed in the lesional skin of SSc patients, suggesting that Fli1 is a potential predisposing factor of SSc reflecting the influence of environmental factors. Consistent with this idea, Fli1 deficiency induces SSc-like phenotypes in dermal fibroblasts and dermal microvascular endothelial cells in vivo and in vitro at molecular levels. Furthermore, Fli1 haploinsufficiency recapitulates tissue fibrosis, vascular activation and inflammation characteristic of SSc to a greater extent in bleomycin-treated mice. Importantly, bosentan, a dual endothelin receptor antagonist with a potential disease-modifying effect on SSc vasculopathy, reverses the expression of Fli1 protein by increasing its protein stability. Therefore, Fli1 may serve as a predisposing factor of SSc and can be a promising therapeutic target of this incurable and devastating disease. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan. Electronic address: yasano-tky@umin.ac.jp.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Asano
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000077300:Bosentan; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051789:Proto-Oncogene Protein c-fli-1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: C497426:Fli1 protein, mouse; D051789:Proto-Oncogene Protein c-fli-1; D013449:Sulfonamides; D001761:Bleomycin; D000077300:Bosentan
keywords: Endothelial cells; Fibroblasts; Fli1; Macrophages; Systemic sclerosis