Center of Experimental Rheumatology, Department of Rheumatology, University of Zurich, Zurich, CH-8952, Switzerland.
Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, B15 2TT, UK.
Sci Rep. 2018 May 9;8(1):7370. doi: 10.1038/s41598-018-24240-2.
DNA methylation is an important epigenetic modification that is known to be altered in rheumatoid arthritis synovial fibroblasts (RASF). Here, we compared the status of promoter DNA methylation of SF from patients with very early RA with SF from patients with resolving arthritis, fully established RA and from non-arthritic patients. DNA was hybridized to Infinium Human methylation 450k and 850k arrays and differential methylated genes and pathways were identified. We could identify a significant number of CpG sites that differed between the SF of different disease stages, showing that epigenetic changes in SF occur early in RA development. Principal component analysis confirmed that the different groups of SF were separated according to their DNA methylation state. Furthermore, pathway analysis showed that important functional pathways were altered in both very early and late RASF. By focusing our analysis on CpG sites in CpG islands within promoters, we identified genes that have significant hypermethylated promoters in very early RASF. Our data show that changes in DNA methylation differ in RASF compared to other forms of arthritis and occur at a very early, clinically yet unspecific stage of disease. The identified differential methylated genes might become valuable prognostic biomarkers for RA development.
DNA 甲基化是一种重要的表观遗传修饰，已知在类风湿关节炎滑膜成纤维细胞（RASF）中发生改变。在这里，我们比较了早期 RA 患者的 SF 与缓解性关节炎、完全确立的 RA 患者和非关节炎患者的 SF 中启动子 DNA 甲基化的状态。DNA 与 Infinium Human methylation 450k 和 850k 阵列杂交，并鉴定了差异甲基化基因和途径。我们可以识别出大量在不同疾病阶段的 SF 之间存在差异的 CpG 位点，表明 SF 中的表观遗传变化在 RA 发展的早期就发生了。主成分分析证实，不同组的 SF 根据其 DNA 甲基化状态分离。此外，途径分析表明，在早期和晚期 RASF 中都改变了重要的功能途径。通过将我们的分析集中在启动子内 CpG 岛中的 CpG 位点上，我们确定了在早期 RASF 中具有显著高甲基化启动子的基因。我们的数据表明，与其他形式的关节炎相比，RASF 中的 DNA 甲基化变化不同，并且发生在疾病的非常早期、临床尚未特异性的阶段。鉴定出的差异甲基化基因可能成为 RA 发展的有价值的预后生物标志物。
