DNA Methylation Marks of COPD

项目总结(见说明)： COPD是美国第四大死因，吸烟已被证明是最重要的环境贡献者。DNA甲基化随年龄和吸烟等环境暴露而变化，是基因表达的关键中介。此外，有数据表明DNA甲基化模式受到DNA多态的影响。虽然在包括肺癌在内的癌症中得到了广泛的研究，但COPD中的变量甲基化及其与基因表达的相关性还没有得到全面的研究。COPD既有局部的肺部表现，也有全身的表现，所有这些都可能受到遗传、基因组和表观遗传途径的影响。我们假设，全基因组DNA甲基化标记的特征将为COPD提供重要的科学见解。我们还假设，表征与IREB2、HHIP和FAM13A变异相关的全基因组DNA甲基化标记可能为调节这三个COPD候选基因提供重要的见解。为了解决这两个假设，该项目的广泛目标包括：1)识别区分COPD易感性和COPD严重程度的甲基化特征；2)使用比较表观遗传学来识别因香烟烟雾暴露而改变的甲基化标记，并可能影响COPD及其组成部分过程、肺气肿和呼吸道疾病的发展。在这个项目中，我们将描述我们肺组织人群中人类受试者的肺组织和血液DNA的全基因组甲基化模式。 野生型C57BL/6(易感)和NZW/LacJ(抗性)小鼠体内暴露在香烟烟雾中后，小鼠肺DNA的甲基化模式也将被表征。我们将使用统计建模和比较表观遗传学来选择COPD候选基因，并使用焦磷酸测序方法在支气管镜检查人群中复制，这是第二个人类队列。该项目将表征对COPD重要的DNA甲基化标记，并将评估作为COPD关键候选基因的IREB2、HHIP和FAM13A变异的表观遗传学影响。我们将使用比较遗传学、翻译遗传学和整合遗传学、基因组学和表观基因组学来确定COPD易感基因的功能特征。我们期望具有重复关联的甲基化标记将为COPD的病理生物学和影响吸烟的表观基因组影响的遗传背景提供新的见解。最后，我们将结合SNP变异、甲基化标记和基因表达数据来定义最全面的COPD因果模型。

PROJECT SUMMARY (See instructions): COPD is the fourth-leading cause of death in the United States, and cigarette smoking has been proven to be the most important environmental contributor. DNA methylation varies with aging and with environmental exposures such as cigarette smoking, and is a critical mediator of gene expression. Additionally, there are data to suggest that DNA methylation patterns are influenced by DNA polymorphisms. Although widely studied in cancers, including lung cancer, the wide-scale investigation of variable methylation in COPD and the correlation with polymorphisms and gene expression have not been comprehensively performed. COPD has both local pulmonary and systemic manifestations, all of which are likely impacted by a combination of genetic, genomic and epigenetic pathways. We hypothesize that characterization of genome-wide DNA methylation marks will provide important scientific insights into COPD. We also hypothesize that characterizing genome-wide DNA methylation marks correlated with IREB2, HHIP and FAM13A variants may provide important insights into regulation of these three COPD candidate genes. To address these two hypotheses, the broad goals of this project include: 1) to identify methylation signatures that discriminate COPD susceptibility and COPD severity and 2) to use comparative epigenetic to identify methylation marks that are altered by cigarette smoke exposure and likely impact the development of COPD and its component processes, emphysema and airway disease. In this project, genome-wide methylation patterns will be characterized for lung tissue and blood DNA from human subjects in our Lung Tissue Population. Methylation patterns will also be characterized for murine lung DNA after in vivo exposure of wild-type C57BL/6 {susceptible) and NZW/LacJ (resistant) mice to cigarette smoke. We will use statistical modeling and comparative epigenetics to select COPD gene candidates to replicate using pyrosequencing methods in the Bronchoscopy Population, a second human cohort. This project will characterize DNA methylation marks important to COPD and will assess the epigenetic impact of variation in IREB2, HHIP and FAM13A as key COPD candidate genes. We will use comparative, translational and integrative genetics, genomics and epigenomics to identify functional features of COPD susceptibility genes. We expect methylation marks with replicated associations will provide novel insights into the pathobiology of COPD and the genetic context that influences the epigenomic impact of cigarette smoking. Lastly, we will integrate SNP variation, methylation marks and gene expression data to define the most comprehensive causal model of COPD.