Towards an understanding of the role of DNA methylation in rheumatoid arthritis: therapeutic and diagnostic implications

Abstract

The term 'epigenetics' loosely describes DNA-templated processes leading to heritable changes in gene activity and expression, which are independent of the underlying DNA sequence. Epigenetic mechanisms comprise of post-translational modifications of chromatin, methylation of DNA, nucleosome positioning as well as expression of noncoding RNAs. Major advances in understanding the role of DNA methylation in regulating chromatin functions have been made over the past decade, and point to a role of this epigenetic mechanism in human disease. Rheumatoid arthritis (RA) is an autoimmune disorder where altered DNA methylation patterns have been identified in a number of different disease-relevant cell types. However, the contribution of DNA methylation changes to RA disease pathogenesis is at present poorly understood and in need of further investigation. Here we review the current knowledge regarding the role of DNA methylation in rheumatoid arthritis and indicate its potential therapeutic implications.

Keywords: DNA methylation; epigenetics; rheumatoid arthritis.

Figure 1.

The DNA demethylation cycle. Cytosine methylation is catalyzed by DNA methyltransferases (DNMTs). 5mC is hydroxylated by the ten–eleven translocation enzymes (TETs) to yield 5-hydroxymethylcytosine (5hmC), which in turn is oxidized to 5fC and 5caC. During passive demethylation, 5hmC, 5fC and 5caC are diluted in a replication dependent manner to regenerate an unmodified C. In a process of active restoration, 5fC and 5caC can be excised by TDG generating an abasic site as part of the base excision repair (BER) process that regenerates unmodified C. Red arrows denote passive DNA demethylation mechanisms and black arrows denote active DNA demethylation.

Figure 2.

Methotrexate (MTX) treatment restores regulatory T cell (Treg) function in rheumatoid arthritis (RA) patients. In MTX naïve RA Tregs, a newly identified differentially methylated region (DMR) is methylated and this is associated with normal Foxp3 expression but reduced CTLA-4 expression. In patients treated with MTX, a reduction in DNMT1 expression correlates with reduced methylation of the DMR in Tregs. This leads to increased Foxp3 expression and a consequential increase in CTLA-4 expression that restores suppressive function. Overall, this suggests that MTX can induce epigenetic modifications in RA Tregs that lead to normal suppressive function and highlight a newly identified mechanism of action for MTX.