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发展。 特定疾病或组织位置的特定途径。以往的研究表明， 类风湿性关节炎（RA）在所有受影响的关节中是相似的。在这里，我们表明，不同的DNA甲基化和 转录组标记不仅区分RA成纤维细胞样滑膜细胞（FLS）与骨关节炎FLS， 还可以区分膝关节和髋关节的RA FLS。使用全基因组方法，我们发现 RA膝关节和髋关节FLS在编码生物学途径的基因甲基化方面的差异，例如 通过JAK-STAT途径的IL-6信号传导。此外，还鉴定了膝关节间的差异表达基因， 和使用RNA-seq的髋关节FLS。这项建议旨在剖析关节特异性表观遗传和功能 RA的方面。为了实现这一目标，我们将1）开发一个高分辨率的关节特异性和疾病图- RA中特异性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应答;以及3）确定 定义关节特异性表观遗传标记，重点是转录因子基序的作用。这些特定的联合 表观遗传和功能特征表明RA疾病机制可能因关节而异， 这可能解释了RA患者药物反应的多样性。

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.