Background/Purpose: Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder that mainly affects the synovial joints, leading to destruction of articular cartilage and bone. There is accumulating evidence for the involvement of epigenetic events in the pathogenesis of RA. Recent genome-wide DNA methylation studies have reported disease-associated changes in DNA methylation profile. However, methylation status-dependent molecular mechanisms that can potentially drive or amplify inflammatory processes in arthritis have not been explored.

Methods: We separated lymphocytes from mice with proteoglycan-induced arthritis (PGIA), an autoimmune model of RA, and surveyed arthritis-induced DNA methylation events at genome-wide level using a Methylated CpG Island Recovery Assay (MIRA)-chip method. In addition, we isolated RNA from lymphocytes of arthritic mice and from peripheral blood mononuclear cells (PBMC) of RA patients, and monitored the DNA methylation-dependent changes in gene expression levels by quantitative RT- PCR. Disease-associated DNA-protein interactions were analyzed using electrophoretic mobility shift assays. A cell culture-based in vitro transient expression system was employed to investigate the functional consequence of the binding of specific transcription factors to gene promoters.

Results: Using the MIRA-chip method, we detected arthritis-associated epigenetic changes that preferentially occurred in B cells from mice with PGIA. Specifically, hypomethylation of the promoter of the gene encoding the “zinc finger and BTB domain containing 38” (ZBTB38) transcription factor resulted in a sharp upregulation of ZBTB38 expression in lymphocytes of arthritic mice relative to non-arthritic animals. Expression of the ZBTB38 gene was also elevated in PBMC of RA patients as compared to its expression in healthy subjects. Moreover, ZBTB38 could facilitate its own transcription, and stimulate the expression of a number of other genes including those encoding transcription factors, pro-inflammatory cytokines, as well as receptors for chemokines and Toll-like receptors. Intriguingly, many of the ZBTB38-targeted genes, identified in this study, have been implicated in RA pathogenesis.

Conclusion: ZBTB38 is involved in an intricate gene regulatory network that seems to control inflammatory processes in RA. Exploration of epigenetic mechanisms involved in the regulation of a major RA-associated inflammatory pathway may lead to identification of new genes as novel biomarkers and potential drug targets for RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epigenetic-control-of-a-gene-regulatory-network-associated-with-experimental-autoimmune-arthritis-and-rheumatoid-arthritis/