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

描述（由申请人提供）：健康的衰老是所有生命的重要组成部分，调节衰老过程中的异常可能导致一系列疾病和残疾，如阿尔茨海默氏症、早衰、心力衰竭、造血功能障碍或癌症。然而，这些过程的分子、遗传和表观遗传调控尚不清楚，并且缺乏这些过程在不同器官系统之间如何不同的知识。虽然先前的研究已经证明，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生物体生命周期中甲基化的组织特异性差异。哺乳动物的器官以不同的速度发育，并且在个体的一生中，暴露于明显不同程度的环境损害或有毒代谢物。这些组织特异性差异可以转化为DNA甲基化和基因表达的重要差异，这些基因表达是控制特定组织中衰老过程所必需的。为了研究这些问题，我建议修改当前的杂交捕获方法，结合下一代测序以及新的计算生物信息学的实施，以精确表征婴儿期和老年小鼠各种器官的整个基因组中每个CpG岛是否存在功能性甲基化。该项目将确定关键的全基因组，年龄相关和组织特异性表观遗传变化，这些变化表明基因的表达或缺乏对适当的组织特异性衰老是必要的。这些知识为探索特定启动子或启动子组的正常甲基化如何改变正常人类衰老和组织特异性疾病中的基因表达的定向研究提供了基础。

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.