Transcription factor Zbtb38 downregulates the expression of anti-inflammatory IL1r2 in mouse model of rheumatoid arthritis.
Transcription factor Zbtb38 downregulates the expression of anti-inflammatory IL1r2 in mouse model of rheumatoid arthritis.
复制标题
DOI：
10.1016/j.bbagrm.2018.09.007
复制
发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
T. Ocskó;D. Tóth;Gyula Hoffmann;Vilmos Tubak;T. Glant;T. Rauch
中科院分区：
文献类型：
--
作者：
T. Ocskó;D. Tóth;Gyula Hoffmann;Vilmos Tubak;T. Glant;T. Rauch
DNA甲基化是基因表达的决定性调节因子。在类风湿关节炎（RA）中描述了差异甲基化启动子，但我们不知道这些突变是如何触发促炎细胞因子环境的。以B细胞为中心的DNA甲基组研究发现，在小鼠类风湿性关节炎模型中，一组基因发生了与疾病相关的变化。在编码转录抑制因子的zbtb38基因的启动子区域检测到关节炎特异性的增殖（低甲基化）。基因表达研究发现，zbtb38启动子的低甲基化伴随着疾病特异性抑制因子的表达，两种抗炎因子白细胞介素1受体2基因（IL1r2）和白细胞介素1受体拮抗剂（IL1rn）均在下调基因之列。我们假设Zbtb38抑制因子可以诱导这些抗炎基因的下调表达，这可能在关节炎的发病机制中起重要作用。我们的研究表明，Zbtb38在B细胞中关节炎相关的增殖（Zbtb38启动子的DNA低甲基化）和il1r2基因的转录沉默之间形成了一个分子桥梁。通过这种方式，疾病相关的DNA低甲基化可以通过干扰抗炎途径来支持自身免疫性关节炎。
DNA methylation is a decisive regulator of gene expression. Differentially methylated promoters were described in rheumatoid arthritis (RA), but we do not know how these epimutations can trigger a proinflammatory cytokine milieu. B cell-focused DNA methylome studies identified a group of genes that had undergone disease-associated changes in a murine model of RA. An arthritis-specific epimutation (hypomethylation) was detected in the promoter region of theZbtb38gene, which encodes a transcriptional repressor. Gene expression studies revealed that hypomethylation of theZbtb38promoter was accompanied by disease-specific repressor expression, and two anti-inflammatory factors interleukin 1 receptor 2 gene (IL1r2) and interleukin-1 receptor antagonist (IL1rn) were among the downregulated genes. We hypothesized that Zbtb38 repressor could induce downregulated expression of these anti-inflammatory genes and that this could significantly contribute to arthritis pathogenesis. Our studies demonstrate that Zbtb38 forms a molecular bridge between an arthritis-associated epimutation (DNA hypomethylation inZbtb38promoter) and transcriptional silencing of theIL1r2gene in B cells. In this way, disease-associated DNA hypomethylation can support autoimmune arthritis by interfering with an anti-inflammatory pathway.