Joint-location specific pathogenic pathways in rheumatoid arthritis

摘要 根据分子签名对患者进行分层可以促进靶向治疗的发展 特定于特定疾病或组织位置的通路。以前的研究表明，糖尿病的发病机制 类风湿性关节炎(RA)在所有受影响的关节中都是相似的。我们在这里展示了不同的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， 但也能区分分离于膝部和臀部的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的差异，如 IL-6通过JAK-STAT途径进行信号传导。此外，膝关节之间的差异表达基因也被鉴定出来。 和HIP FLS使用RNA-seq。这项建议旨在剖析关节特有的表观遗传学和功能性 RA的方方面面。为了实现这一点，我们将1)开发一张高分辨率的关节特定和疾病地图- RA中特定的DNA甲基化模式包括整合基因组学和 转录组数据；2)通过评估确定差异表观遗传标记的功能后果 关节特异的FLS转录组模式和细胞因子反应；以及3)决定 定义联合的特定表观遗传标记，重点关注转录因子基序的作用。这些关节特定 表观遗传学和功能特征表明，类风湿性关节炎的发病机制可能因关节而异 这可能解释了类风湿关节炎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.