Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes.
Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes.
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类风湿关节炎中关节特异性 DNA 甲基化和转录组特征识别不同的致病过程
DOI：
10.1038/ncomms11849
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发表时间：
2016-06-10
影响因子：
16.6
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Ai R;Hammaker D;Boyle DL;Morgan R;Walsh AM;Fan S;Firestein GS;Wang W
根据分子签名对患者进行分层可以促进针对特定疾病或组织位置的特定路径的治疗学的发展。以往的研究表明，类风湿性关节炎(RA)的发病机制在所有受累关节中都是相似的。在这里，我们表明，不同的DNA甲基化和转录组特征不仅区分RA成纤维细胞样滑膜细胞(FLS)和骨关节炎FLS，也区分从膝盖和髋部分离的RA FLS。使用全基因组方法，我们显示了RA膝关节和髋关节FLS在编码生物途径的基因甲基化方面的差异，例如通过JAK-STAT途径的IL-6信号转导。此外，利用RNA测序技术鉴定了膝关节和髋关节FLS之间的差异表达基因。差异甲基化和表达的双重证据基因包括多个HOX基因。关节特异的DNA标记表明，不同关节的RA疾病机制可能不同，从而潜在地解释了RA患者药物反应的一些多样性。
Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multipleHOXgenes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients.