RNA Editing–Associated Post-Transcriptional Gene Regulation in Rheumatoid Arthritis

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterised by systemic inflammation of joints. The observed complexity of RA pathogenesis and studies that have been carried out so far indicate that RA pathogenesis is regulated at multiple levels. Given the role of RNA editing in autoimmune disease, we hypothesised that RNA editing could contribute to RA pathogenesis by regulating gene expression through post-transcriptional mechanisms. METHODS: We identified RNA editing events in synovial tissues from early and established RA compared with normal subjects from an available transcriptome data set using REDItools. To investigate the potential effect of these RNA editing events on gene expression, we carried out an analysis of differential exon usage in the vicinity of the differentially edited sites using DEXSeq. We then used STRING to identify putative interactions between differentially edited genes identified from REDItools analysis. We also investigated the possible effects of these RNA editing events on miRNA-target mRNA interactions as predicted by miRanda. RESULTS: Our analysis revealed that there is extensive RNA editing in RA, with 304 and 273 differentially edited events in early RA and established RA, respectively. Of these, 25 sites were within 11 genes in early RA, and 34 sites were within 7 genes in established RA. DEXSeq analysis revealed that RNA editing correlated with differential exon usage in 4 differentially edited genes that have previously also been associated with RA in some measure: ATM, ZEB1, ANXA4, and TIMP3. DEXSeq analysis also revealed enrichment of some non-functional isoforms of these genes, perhaps at the expense of their full-length counterparts. Network analysis using STRING showed that several edited genes were part of the p53 protein-protein interaction network. We also identified several putative miRNA binding sites in the differentially edited genes that were lost upon editing. CONCLUSIONS: Our results suggested that the expression of genes involved in DNA repair and cell cycle, including ATM and ZEB1 which are well-known functional regulators of the DNA damage response pathway, could be regulated by RNA editing in RA synovia. This may contribute to an impaired DNA damage response in synovial tissues.