Joint-location specific pathogenic pathways in rheumatoid arthritis

摘要 根据分子特征对患者进行分层可以促进靶向治疗的开发 特定于特定疾病或组织位置的途径。先前的研究表明，发病机制 类风湿性关节炎 (RA) 在所有受影响的关节中都是相似的。在这里，我们展示了不同的 DNA 甲基化和 转录组特征不仅可以区分 RA 成纤维细胞样滑膜细胞 (FLS) 和骨关节炎 FLS， 还可以区分从膝盖和臀部分离的 RA FLS。使用全基因组方法，我们发现 RA膝关节和髋关节FLS在编码生物通路的基因甲基化方面存在差异，例如 通过 JAK-STAT 途径的 IL-6 信号传导。此外，还鉴定了膝关节之间的差异表达基因。 和使用 RNA-seq 的髋关节 FLS。该提案旨在剖析关节特异性表观遗传和功能 RA 的各个方面。为了实现这一目标，我们将 1）开发关节特异性和疾病的高分辨率图 - RA 中特定的 DNA 甲基化模式，包括整合基因组学和 转录组学数据； 2) 通过评估确定差异表观遗传标记的功能后果 关节特异性 FLS 转录组模式和细胞因子反应； 3）确定机制 定义关节特异性表观遗传标记，重点关注转录因子基序的作用。这些联合特有的 表观遗传和功能特征表明，RA 疾病机制可能因关节而异，并且 可能解释 RA 患者药物反应的一些多样性。

ABSTRACT 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 discovered differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signaling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-seq. This proposal is designed to dissect joint-specific epigenetic and functional aspects of RA. To accomplish this, we will 1) develop a high resolution map of joint-specific and disease- specific DNA methylation patterns in RA including pathway analysis that integrates genomics and transcriptomics data; 2) determine the functional consequences of differential epigenetic marks by evaluating joint-specific FLS transcriptome patterns and cytokine responses; and 3) determine the mechanisms that define joint specific epigenetic marks, with a focus on the role of transcription factor motifs. These joint-specific epigenetic and functional signatures suggest that RA disease mechanisms might vary from joint to joint and potentially explain some of the diversity of drug responses in RA patients.