Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts
Arthritis & Rheumatism: Official Journal of the American College …, 2006•Wiley Online Library
Abstract Objective Scleroderma (systemic sclerosis; SSc) is an autoimmune disease
characterized by vasculopathy and widespread organ fibrosis. Altered fibroblast function,
both in vivo and in vitro, is well documented and illustrated by augmented synthesis and
deposition of extracellular matrix proteins. We undertook this study to investigate the
possibility that epigenetic mechanisms mediate the emergence and persistence of the
altered SSc fibroblast phenotype. Methods The effects of DNA methyltransferase and …
characterized by vasculopathy and widespread organ fibrosis. Altered fibroblast function,
both in vivo and in vitro, is well documented and illustrated by augmented synthesis and
deposition of extracellular matrix proteins. We undertook this study to investigate the
possibility that epigenetic mechanisms mediate the emergence and persistence of the
altered SSc fibroblast phenotype. Methods The effects of DNA methyltransferase and …
Objective
Scleroderma (systemic sclerosis; SSc) is an autoimmune disease characterized by vasculopathy and widespread organ fibrosis. Altered fibroblast function, both in vivo and in vitro, is well documented and illustrated by augmented synthesis and deposition of extracellular matrix proteins. We undertook this study to investigate the possibility that epigenetic mechanisms mediate the emergence and persistence of the altered SSc fibroblast phenotype.
Methods
The effects of DNA methyltransferase and histone deacetylase inhibitors on collagen expression and the level of epigenetic mediators in fibroblasts were examined. The effects of transient transfection of SSc fibroblasts with FLI1 gene and normal cells with FLI1 antisense construct on collagen expression were determined. The methylation status of the FLI1 promoter was tested in cultured cells and in SSc and normal skin biopsy specimens.
Results
Increased levels of epigenetic mediators in SSc fibroblasts were noted. The addition of epigenetic inhibitors to cell cultures normalized collagen expression in SSc fibroblasts. The augmented collagen synthesis by SSc fibroblasts was linked to epigenetic repression of the collagen suppressor gene FLI1. Heavy methylation of the CpG islands in the FLI1 promoter region was demonstrated in SSc fibroblasts and skin biopsy specimens.
Conclusion
The results of this study indicate that epigenetic mechanisms may mediate the fibrotic manifestations of SSc. The signal transduction leading to the SSc fibrotic phenotype appears to converge on DNA methylation and histone deacetylation at the FLI1 gene.
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