Abstract
In rheumatoid arthritis (RA), synovial fibroblasts (SFs) produce a variety of pathogenic molecules in the inflamed synovium. Despite their potential importance, comprehensive genetic network of SFs under inflammatory conditions remains elusive. Here, to elucidate the actions of SFs and their contributions to RA pathogenesis, SFs, stimulated with 8 proinflammatory cytokines, were analyzed using genomic, epigenomic and transcriptomic approaches. SFs exposed to synergistically acting cytokines produced markedly higher levels of pathogenic molecules, including CD40 whose expression was significantly affected by a RA risk SNP (rs6074022). Upon chromatin remodeling in activated SFs, RA risk loci were enriched in clusters of enhancers (super-enhancers; SEs) induced by synergistic proinflammatory cytokines. A RA risk SNP (rs28411362), located in a SE under synergistically acting cytokines, formed three-dimensional contact with the promoter of MTF1 gene, whose binding motif showed significant enrichment in stimulation specific-SEs. Consistently, inhibition of MTF1 suppressed cytokine and chemokine production from SFs and ameliorated mice model of arthritis. These results indicate that epigenomic and transcriptomic parsing of transformed SFs under the inflammatory environment yields potential therapeutic targets associated with genetic risk of RA.
One Sentence Summary SFs under synergistic inflammation is associated with RA heritability, and MTF1 and RUNX1 could be crucial for the pathogenic chromatin rearrangement.
Footnotes
Figure 6 and 7 reviesed; Supplemental files updated.