Molecular mechanisms of histone deacetylases in rheumatoid arthritis fibroblast-like synoviocytes

Histones modifying enzymes comprise a class of epigenetic regulators that, by controlling chromatin accessibility and transcriptional initiation, insure correct cellular and inflammatory responses. Among these, histone acetyltransferases (HAT) mediate the transfer of acetyl groups from acetyl coenzyme A (acetyl-CoA) to the ε-amino groups of lysine residues, while HDACs counterbalance HAT activity by deacetylating histones and non-histone proteins. The balance between HAT and HDAC activity has often been found deregulated in pathological conditions, including RA and other forms of chronic inflammatory diseases. Specifically, at the initiation of this thesis research, increased HDAC activity and expression were reported in cells and tissue from RA patients, and associated with the production of synovial inflammatory mediators. The studies presented in this thesis were designed with the intention to characterize the expression and activity of class I and class II histone deacetylases (HDACs) in rheumatoid arthritis (RA) synovial tissue and fibroblasts-like synoviocytes (FLS), and to identify the molecular and anti-inflammatory mechanisms of action of broad- and isoform-selective HDAC inhibitors (HDACi).