Bromodomain proteins in the pathogenesis and therapy of RA
Bromodomain proteins are readers of the ε-N-acetylation of lysine residues (Kac) on histone tails, a modification that is associated with an open chromatin architecture and transcriptional activation. In recent years, pan-inhibitors have been developed targeting different families of bromodomain proteins. Some of these inhibitors have potent anti-inflammatory capacities and showed beneficial effects in models of arthritis. We showed that I-BET, a small molecule inhibitor targeting the BET protein family members (BRD2, BRD3, BRD4), suppressed the expression of a broad range of inflammatory mediators and matrix degrading enzymes in RA synovial fibroblasts in presence of cytokines or Toll-like receptor ligands. Furthermore, we have identified BET reading as one of the epigenetic events contributing to the positional identity of synovial fibroblasts from different joint localizations, which was independent of an inflammatory stimulus. Based on these findings we are investigating the function of individual bromodomain proteins in regulating the inflammatory response in synovial fibroblast as well as in maintaining their joint specific patterns.
Researcher in charge
Prof Christina Nevado, Department of Chemistry, University of Zurich
Dr Wei-Lynn Wong, Institute of Experimental Immunology, University of Zurich
Prof Kris Reedquist, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht
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