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.

Keywords::

• DNA methylation
• epigenetics
• histone modifications
• SSc fibroblasts

Financial & competing interests disclosure

Astrid Jüngel has received funding from FP7 Maserswitch and Zurich Center of Integrative Physiology. Jörg Distler is a consultant for Actelion Pharmaceuticals, Pfizer, GlaxoSmithKline, Bayer Schering Pharma and Celgene, and has received grant support from Bayer Schering Pharma, Celgene, Ergonex Pharma, Novartis, NiCox, Array Biopharma and Bristol-Myers Squibb. Steffen Gay has received funding from IAR-EPALINGES and FP7 Masterswitch. Oliver Distler is a consultant for, and received funding from, Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Novartis and Active Biotec in the area of potential treatments of scleroderma and its complications. Lecture honoraria from Actelion, Pfizer and Ergonex. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.