Abstract
DNA methylation is an important epigenetic modification that is known to be altered in rheumatoid arthritis synovial fibroblasts (RASF). Here, we compared the status of promoter DNA methylation of SF from patients with very early RA with SF from patients with resolving arthritis, fully established RA and from non-arthritic patients. DNA was hybridized to Infinium Human methylation 450k and 850k arrays and differential methylated genes and pathways were identified. We could identify a significant number of CpG sites that differed between the SF of different disease stages, showing that epigenetic changes in SF occur early in RA development. Principal component analysis confirmed that the different groups of SF were separated according to their DNA methylation state. Furthermore, pathway analysis showed that important functional pathways were altered in both very early and late RASF. By focusing our analysis on CpG sites in CpG islands within promoters, we identified genes that have significant hypermethylated promoters in very early RASF. Our data show that changes in DNA methylation differ in RASF compared to other forms of arthritis and occur at a very early, clinically yet unspecific stage of disease. The identified differential methylated genes might become valuable prognostic biomarkers for RA development.
Highlights
Rheumatoid arthritis (RA) is a chronic, destructive autoimmune arthritis that affects 0.5–1% of the population worldwide
We focused our analysis on promoter regions, as promoter DNA methylation is most likely to have an impact on gene expression
Principal component analysis (PCA) showed that DMPs separated SF according to both disease groups and disease stage (Figure 1A)
Summary
Rheumatoid arthritis (RA) is a chronic, destructive autoimmune arthritis that affects 0.5–1% of the population worldwide. Many patients develop unspecific symptoms and signs of systemic autoimmunity i.e. auto-antibodies years before disease onset[1]. Changes in DNA methylation have long been recognized in synovial fibroblasts of RA patients (RASF)[2,3,4] and pathway analysis of differentially methylated sites (DMS) suggested that these changes affect genes previously implicated in the pathogenesis of RA5. It is assumed that changes in DNA methylation contribute to the activated and destructive phenotype of RASF. Two aspects in the analysis of DNA methylation in RASF, have not been addressed until now It is not known whether changes in DNA methylation are a cause or a consequence of the chronic inflammatory process in RA. It is difficult to estimate which changes in DNA methylation are RA specific and which are OA specific and it is unknown up to now how changes found in RASF compare to other inflammatory arthitides
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