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Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

By Haruka Tsuchiya, Mineto Ota, Shuji Sumitomo, Kazuyoshi Ishigaki, Akari Suzuki, Toyonori Sakata, Yumi Tsuchida, Hiroshi Inui, Jun Hirose, Yuta Kochi, Yuho Kadono, Katsuhiko Shirahige, Sakae Tanaka, Kazuhiko Yamamoto, Keishi Fujio

Posted 03 Dec 2019
bioRxiv DOI: 10.1101/861781 (published DOI: 10.1136/annrheumdis-2020-218189)

Objectives Synovial fibroblasts (SFs) produce a variety of pathogenic molecules in the inflamed synovium of rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating the genetic contribution to molecular regulatory networks under inflammatory condition. Methods SFs from RA and osteoarthritis (OA) patients (n=30 each) were stimulated with 8 different cytokines (IFN-α, IFN-γ, TNF-α, IL-1β, IL-6/sIL-6R, IL-17, TGF-β1, IL-18) or a combination of all 8 (8-mix). Peripheral blood mononuclear cells (PBMCs) from the same patients were fractioned into five major immune cell subsets (CD4+ T cells, CD8+ T cells, B cells, NK cells, monocytes). Integrative analyses including mRNA expression, histone modifications (H3K27ac, H3K4me1, H3K4me3), 3D genome architecture and genetic variations of SNPs were performed. Results 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. Conclusions Our findings established the dynamic landscape of activated SFs, and yielded potential therapeutic targets associated with genetic risk of RA. ### Competing Interest Statement The authors have declared no competing interest.

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