Imgenberg-Kreuz Juliana, Sandling Johanna K, Almlöf Jonas Carlsson, Nordlund Jessica, Signér Linnea, Norheim Katrine Braekke, Omdal Roald, Rönnblom Lars, Eloranta Maija-Leena, Syvänen Ann-Christine, Nordmark Gunnel
Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Ann Rheum Dis. 2016 Nov;75(11):2029-2036. doi: 10.1136/annrheumdis-2015-208659. Epub 2016 Feb 8.
Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.
Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.
We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.
Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.
越来越多的证据表明表观遗传学在自身免疫性疾病（包括原发性干燥综合征，pSS）的发病机制中发挥作用。本研究的目的是通过分析患者和对照的多种组织来研究DNA甲基化在pSS中的作用。
使用HumanMethylation450K芯片对全血、CD19+B细胞和小唾液腺活检组织进行全基因组DNA甲基化谱分析。通过RNA测序分析CD19+B细胞中的基因表达。对已知pSS风险位点的DNA甲基化进行遗传调控效应分析。
我们在全血和CD19+B细胞中发现干扰素（IFN）调控基因存在显著低甲基化，包括MX1、IFI44L和PARP9基因，这重复了之前pSS的报道，同时还发现了大量新的关联。观察到与增强子和启动子区域的组蛋白标记的基因组重叠富集。我们首次表明，pSS B细胞中IFN调控基因的低甲基化与其表达增加有关。在小唾液腺活检组织中，我们观察到IFN诱导基因OAS2存在低甲基化。通路和疾病分析导致抗原呈递、IFN信号传导和淋巴细胞增殖性疾病的富集。观察到已知pSS风险位点甲基化水平受遗传控制的证据。
我们的研究强调了IFN诱导基因的表观遗传调控在pSS中的作用，新发现需要重复验证。与基因表达改变的关联提示了pSS病因中差异甲基化CpG位点的功能机制。
