High resolution DNA methylation signature in rheumatoid arthritis

描述(申请人提供)：类风湿性关节炎(RA)的关节损害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发炎组织中的环境暴露和压力如何改变基因表达和细胞功能。研究最深入的机制之一是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，由DNA甲基转移酶(DNMT)介导。甲基化状态受环境或胚胎发育过程中预编程事件的影响。DNMT的表达可以在细胞分裂过程中维持甲基化，从而在子细胞中保留来自环境的细胞印记。甲基化模式的异常在各种疾病中都有描述，最明显的是癌症，在癌症中，高甲基化和低甲基化的CpG基因座可以抑制关键的癌基因。自身免疫也与甲基化改变有关，例如小鼠的狼疮样疾病、RA滑膜，可能还有RA滑膜细胞。我们最近发现，RA滑膜细胞表现出一种独特的DNA甲基化模式，可以调节关键基因的表达。在这个提案中，我们将扩展RA的DNA甲基化签名，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。还将进行其他研究，以确定转录因子基序如何塑造疾病特有的甲基化模式，即使DNMT酶的数量有限。这一假设将通过1)精炼DNA甲基化以在RA成纤维样滑膜细胞(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了解RA FLS功能的统一方法；以及3)确定转录因子基序如何对独特的RA甲基组信号起作用。

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.