High resolution DNA methylation signature in rheumatoid arthritis

描述（由申请人提供）：类风湿性关节炎（RA）的关节损伤和滑膜炎症受遗传和环境因素的影响。 表观遗传学提供了新的方法来思考环境暴露和炎症组织中的压力如何改变基因表达和细胞功能。 研究得最多的机制之一是DNA甲基化，它可以通过抑制基因表达来深刻改变细胞功能。 甲基化通常发生在CpG基因座上，并由DNA甲基转移酶（DNMT）介导。 甲基化状态受环境或通过胚胎发育期间的预编程事件影响。 DNMT表达可以在细胞分裂期间保持甲基化，从而在子细胞中保护细胞印记不受环境影响。 甲基化模式的缺失已在多种疾病中描述，最显著的是癌症，其中高甲基化和低甲基化的CpG基因座可去抑制关键癌基因。 自身免疫也与甲基化改变有关，如小鼠、RA滑膜和可能的RA滑膜细胞中的狼疮样疾病。 我们最近发现，RA滑膜细胞表现出独特的DNA甲基化模式，可以调节关键基因的表达。 在这项提案中，我们将扩大RA的DNA甲基化特征，并将这些信息与基因组和转录组数据相结合，以确定参与疾病的关键基因。 将进行额外的研究以确定转录因子基序如何形成疾病特异性甲基化模式，即使存在有限数量的DNMT酶。 该假设将通过以下方式进行探索：1）改进DNA甲基化以在RA成纤维细胞样滑膜细胞（FLS）中创建高分辨率图谱; 2）整合基因组、表观基因组和转录组数据以创建理解RA FLS功能的统一方法;以及3）确定转录因子基序如何促成独特的RA甲基化组特征。

DESCRIPTION (provided by applicant): Joint damage and synovial inflammation in rheumatoid arthritis (RA) are influenced by genetic and environmental factors. Epigenetics offers new ways to think about how environmental exposure and stress in inflamed tissues can alter gene expression and cellular function. One of the best-studied mechanisms is DNA methylation, which can profoundly alter cellular function by repressing gene expression. Methylation typically occurs on CpG loci and is mediated by DNA methyltransferases (DNMTs). Methylation status is influenced by the environment or through pre-programmed events during embryonic development. DNMT expression can maintain methylation during cell division, thus preserving the cellular imprinting from the environment in daughter cells. Abnormalities in methylation patterns have been described in a variety of diseases, most notably cancer where hyper- and hypo-methylated CpG loci can de-repress critical oncogenes. Autoimmunity has also been associated with altered methylation, such as lupus-like diseases in mice, RA synovium, and possibly RA synoviocytes. We recently showed that RA synoviocytes exhibit a distinct DNA methylation pattern that can regulate expression of key genes. In this proposal, we will expand the DNA methylation signature of RA and integrate this information with genomic and transcriptomic data to identify key genes that participate in the disease. Additional studies will be performed to determine how transcription factor motifs can shape disease specific methylation pattern even though there are a limited number of DNMT enzymes. This hypothesis will be explored by 1) refining the DNA methylation to create a high resolution map in RA fibroblast- like synoviocytes (FLS); 2) integrating genomic, epigenomic, and transcriptomic data to create a unified approach to understanding RA FLS function; and 3) determine how transcription factor motifs contribute to the unique RA methylome signature.