Epigenetics

«Epigenetics» refers to modifications of chromatin and DNA that even though being heritable don't change the nucleotide code of the DNA. Epigenetic systems studied in the Center of Experimental Rheumatology include methylation of DNA and histones, and acetylation of histones (Fig 1). Thereby, the influence of these modifications on the development of rheumatoid arthritis and scleroderma is being analyzed. In particular, we are interested in how these modifications are involved in the production of disease-mediating factors produced by fibroblasts (synovial fibroblasts, skin fibroblasts). In this regard, also therapeutic possibilities that emerge from the modulation of key enzymes in this epigenetic system (histone acetylases, histone deacetylases) are tested.

Another aspect of epigenetics is the regulation of gene expression by microRNAs (miRNAs). miRNAs are small (18-24 nucleotides), endogenous, single-stranded, non-coding RNAs, which post-transcriptionally regulate gene expression. Up to now already more than 400 different miRNAs have been discovered, but it is assumed that they actually constitute 2-3% of the human genome. Even though the biological functions of most of the miRNAs are not clearly known, the fact that they are predicted to regulate around 30% of all genes suggests a key involvement in the development of various diseases. In our lab dysregulation of miRNAs is analyzed in patients with rheumatoid arthritis and scleroderma. The impact of selected miRNAs that are found to be differentially expressed in patients, is analyzed with over-expression (pre-miRNA) or silencing (antago-miRNA) experiments (Fig 2). Thereby their influence on the expression of disease-modifying genes can be elucidated.

Publications

Karouzakis E, Neidhart M, Gay RE, Gay S. Molecular and cellular basis of rheumatoid joint destruction. Immunol Lett. 2006, 106:8-13.

Huber LC, Distler JH, Moritz F, Hemmatazad H, Hauser T, Michel BA, Gay RE, Matucci-Cerinic M, Gay S, Distler O, Jüngel A. Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycininduced skin fibrosis. Arthritis Rheum 2007, 56:2755-64.

Huber LC, Brock M, Hemmatazad H, Giger OT, Moritz F, Trenkmann M, Distler JH, Gay RE, Kolling C, Moch H, Michel BA, Gay S, Distler O, Jüngel A. Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum 2007, 56:1087-93.

Stanczyk J, Leslie Pedrioli DM, Brentano F, Sanchez-Pernaute O, Kolling C, Gay RE, Detmar M, Gay S, Kyburz D. Altered expression of microRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 2008. In press.

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