A Gene Regulatory Network Controlled by Transcription Factor ZBTB38 in RA

Rush University Medical Center, Chicago IL

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Abstract

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA)-associated cytokine networks, cellular receptors, and signal transduction pathways have been fairly well characterized. However, gene regulatory networks that may drive and amplify inflammatory processes in RA have not been explored. Using mice with cartilage proteoglycan (PG)-induced arthritis (an autoimmune animal model of RA), we detected arthritis-specific epigenetic changes in B lymphocytes, which caused markedly upregulated expression of the gene encoding the zinc finger and BTB domain containing 38 (ZBTB38) transcription factor. The ZBTB38 gene was similarly upregulated in lymphocytes of the majority of tested RA patients as compared to healthy individuals. We also found that ZBTB38 could facilitate its own transcription, and stimulate the expression of a number of other genes including those coding for transcription factors, pro-inflammatory cytokines, as well as chemokine and Toll-like receptors. Intriguingly, many of the gene products affected by ZBTB38's transcription factor activity have been implicated in RA pathogenesis. Our preliminary data argue for the involvement of ZBTB38 in an intricate gene regulatory network that controls inflammatory/autoimmune processes in RA. We will identify the members of this network and delineate their interactions in lymphocytes from arthritic mice and from patients with RA. In addition, we will further investigate arthritis-relate epigenetic events in selected RA patients. The proposed project should help in exploring genetic/epigenetic mechanisms involved in the regulation of a major RA- associated inflammatory pathway, and may also identify genes as novel biomarkers and drug targets for RA.