AGE AND TISSUE-SPECIFIC CHANGES IN GENOME-WIDE MAMMALIAN METHYLATION

描述（由申请人提供）：健康衰老是所有生命的重要组成部分，衰老调节过程的失常可能导致多种疾病和残疾，例如阿尔茨海默病、过早衰老、心力衰竭、造血功能障碍或癌症。然而，人们对这些过程的分子、遗传和表观遗传调控知之甚少，并且缺乏对这些过程在不同器官系统之间有何差异的了解。虽然之前的研究已经证明衰老与哺乳动物基因组甲基化总体水平的普遍下降有关，但这些研究并没有关注哺乳动物有机体生命周期中甲基化的组织特异性差异。哺乳动物器官以不同的速度发育，并且在个体的一生中，暴露于显着不同水平的环境侵害或有毒代谢物。这些组织特异性差异可能转化为 DNA 甲基化和特定组织内适当控制衰老过程所需基因表达的重要差异。为了研究这些问题，我建议结合下一代测序修改当前的杂交捕获方法，并实施新的计算生物信息学，以精确表征婴儿和老年小鼠的各种器官的整个基因组中每个 CpG 岛是否存在功能甲基化。该项目将鉴定关键的全基因组、与年龄相关和组织特异性的表观遗传变化，表明其表达或缺乏的基因对于适当的组织特异性衰老是必需的。这些知识为定向研究奠定了基础，以探索特定启动子或启动子组正常甲基化的破坏如何改变正常人类衰老和组织特异性疾病中的基因表达。

DESCRIPTION (provided by applicant): Healthy aging is a critical part of all life, and aberrations in the processes that regulate aging can result in a wide array of disease and disability such as Alzheimer's, premature aging, heart failure, hematopoietic dysfunction, or cancer. Nevertheless, the molecular, genetic and epigenetic regulation of these processes is poorly understood, and knowledge of how these processes differ between various organ systems is lacking. While prior studies have demonstrated that aging is associated with a general decrease in the overall level of methylation across a mammalian genome, these studies have not focused on tissue-specific differences in methylation over the lifespan of a mammalian organism. Mammalian organs develop at different rates and, over the lifespan of an individual, are exposed to significantly different levels of environmental insults or toxic metabolites. These tissue-specific differences could translate to important differences in DNA methylation and the expression of genes necessary to control the aging process appropriately within a given tissue. To study these questions, I propose to modify current hybridization capture methods in conjunction with next-generation sequencing along with the implementation of new computational bioinformatics to precisely characterize the presence or absence of functional methylation at each CpG island across the entire genome from a variety of organs in infantile and aged mice. This project will identify critical genome-wide, age-related and tissue-specific epigenetic changes suggesting genes whose expression, or lack thereof, is necessary for proper tissue- specific aging. Such knowledge provides the foundation for directed studies to explore how disruption of normal methylation at specific promoters or groups of promoters alters gene expression in normal human aging and tissue-specific disease.