High resolution DNA methylation signature in rheumatoid arthritis

类风湿性关节炎的高分辨率 DNA 甲基化特征

• 批准号: 8897270
• 负责人: GARY S FIRESTEIN
• 金额: $ 34.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897270
• 关键词: Acetylation; Affect; Autoimmunity; Behavior; Binding; Cell Line; Cell division; Cell physiology; Cells; Code; Computational Technique; CpG Islands; Critical Pathways; DNA Methylation; DNA Modification Methylases; Data; Data Set; Databases; Degenerative polyarthritis; Disease; Embryonic Development; Employee Strikes; Environment; Environmental Exposure; Environmental Risk Factor; Enzymes; Epigenetic Process; Evaluation; Event; Exhibits; Fibroblasts; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Goals; Health; Histones; Individual; Inflammatory; Inflammatory Arthritis; Malignant Neoplasms; Maps; Mediating; Methylation; MicroRNAs; Mus; Oncogenes; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Play; Predisposition; RNA; Resolution; Rheumatoid Arthritis; Role; Series; Severities; Shapes; Signal Transduction; Stress; Synovial Membrane; Synovitis; System; Therapeutic Agents; Tissues; United States National Institutes of Health; base; cytokine; daughter cell; epigenomics; genome wide association study; genome-wide; imprint; insight; joint injury; lupus-like; methylation pattern; methylome; new therapeutic target; novel therapeutics; programs; protein protein interaction; transcription factor; transcriptomics

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.

描述（由申请人提供）：类风湿性关节炎（RA）中的关节损伤和滑膜炎症受到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炎症组织中的环境暴露和压力如何改变基因表达和细胞功能。 研究得最好的机制之一是 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 位点上，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 表达可以在细胞分裂过程中维持甲基化，从而保留子细胞中环境的细胞印记。 甲基化模式的异常在多种疾病中都有描述，最明显的是癌症，其中高甲基化和低甲基化的 CpG 位点可以解除对关键癌基因的抑制。 自身免疫也与甲基化改变有关，例如小鼠狼疮样疾病、RA滑膜以及可能的RA滑膜细胞。 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，我们将扩展 RA 的 DNA 甲基化特征，并将这些信息与基因组和转录组数据整合，以确定参与该疾病的关键基因。 尽管 DNMT 酶的数量有限，但仍将进行其他研究以确定转录因子基序如何塑造疾病特异性甲基化模式。 该假设将通过以下方式进行探索：1) 精炼 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，创建统一的方法来理解 RA FLS 功能； 3) 确定转录因子基序如何促成独特的 RA 甲基化组特征。