title: Epigenetic modifications: novel therapeutic strategies for systemic sclerosis?
abstract: Epigenetic modifications of gene expression comprise modifications of DNA by DNA methylation and modifications of the histone proteins by acetylation, methylation, SUMOylation or phosphorylation. DNA methylation in the promoter region of genes represses gene transcription. Histone modifications influence the structure of DNA and regulate gene expression by changing the availability of DNA for the transcriptional machinery or DNA-binding proteins. Histone modifications are mediated by enzymes and induce or repress gene expression. Aberrant expression of single enzymes disturb the normal balance of these modifiers leading to cancer or autoimmune diseases. We show in this article that epigenetic modifications contribute to the massive production of extracellular matrix proteins in systemic sclerosis skin fibroblasts. Both DNA methylation and histone modifications contribute to the activated phenotype of systemic sclerosis fibroblasts. In vitro and in vivo experiments demonstrate that the use of epigenetic-based drugs on these cells is able to reverse their activated phenotype.
authors.affiliation: Center of Experimental Rheumatology, University Hospital Zurich, Zurich Center of Integrative Human Physiology, Switzerland.
authors.forename: Astrid
authors.initials: A
authors.lastname: Jüngel
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
mesh_terms: D000818:Animals; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D044127:Epigenesis, Genetic / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology; D005355:Fibrosis / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D012595:Scleroderma, Systemic / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
chemical_list: C526317:CCN2 protein, human; D056572:Histone Deacetylase Inhibitors; D047495:PPAR gamma; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D015254:DNA Modification Methylases