Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Interleukin 1 beta (IL1B) is a multifunctional cytokine that is highly expressed in rheumatoid arthritis (RA) and drives pro-inflammatory pathways via interleukin 1 receptor 1 (IL1R1)-mediated signaling. IL1B-specific receptor, IL1r2 is a decoy receptor that can sequester IL1B and acts as an anti-inflammatory factor. We investigated how an arthritis-specific epigenetic event is connected with the suppressed expression of anti-inflammatory IL1r2. The main goal of the current study is to explore gene regulatory pathways are involved in arthritis.
Methods: Disease-associated DNA methylation profiles analyses were conducted by methylated CpG island recovery assay (MIRA-chip) in arthritic B cells. Gene expression changes were investigated by microarray platforms and quantitative real-time polymerase chain reaction (RT-qPCR). Targeted gene silencing was carried out by electroporation of gene-specific shRNA expressing plasmids, and gene expression changes were monitored using RT–qPCR and Western blotting. Transient transfection studies were used for functional characterization of IL1r2 promoter.
Results: The promoter region of Zbtb38 transcription factor encoding gene was differentially methylated in B cells isolated from arthritic mice, which hypomethylation resulted in high expression of Zbtb38. Zbtb38 directly regulates IL1r2 gene expression and initiates its silencing in arthritic B cells. AhR transcription factor is also intimately involved in transcriptional regulation of IL1r2 and acts against Zbtb38. The fine balance of these two transcription factors can define the actual expression status of IL1r2 gene.
Conclusion: Zbtb38 forms a molecular bridge between an arthritis-associated epigenetic alteration (i.e., de novo DNA hypomethylation in Zbtb38 promoter) and transcriptional silencing of IL1r2 gene in arthritic B cells. In this context, Zbtb38 works as a potent repressor that turns off an anti-inflammatory pathway and significantly contributes to pathogenesis of arthritis.
To cite this abstract in AMA style:Ocskó T, Tóth DM, Balog A, Mikecz K, Glant TT, Rauch TA. DNA Hypomethylation in Promoter Region of Zbtb38 Gene Ultimately Leads to Downregulated Expression of Anti-Inflammatory IL1r2 in Experiential Model of Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/dna-hypomethylation-in-promoter-region-of-zbtb38-gene-ultimately-leads-to-downregulated-expression-of-anti-inflammatory-il1r2-in-experiential-model-of-rheumatoid-arthritis/. Accessed August 4, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dna-hypomethylation-in-promoter-region-of-zbtb38-gene-ultimately-leads-to-downregulated-expression-of-anti-inflammatory-il1r2-in-experiential-model-of-rheumatoid-arthritis/