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

描述(申请人提供)：健康的衰老是所有生命的关键部分，调节衰老的过程中的异常可能会导致一系列的疾病和残疾，如阿尔茨海默氏症、过早衰老、心力衰竭、造血功能障碍或癌症。然而，对这些过程的分子、遗传和表观遗传调控知之甚少，也缺乏关于这些过程在不同器官系统之间如何不同的知识。虽然先前的研究表明，衰老与哺乳动物基因组整体甲基化水平的普遍下降有关，但这些研究并未集中于哺乳动物生物生命周期中甲基化水平的组织特异性差异。哺乳动物的器官发育速度不同，在人的一生中，暴露在明显不同程度的环境侮辱或有毒代谢物中。这些特定组织的差异可能会转化为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，我建议修改目前的杂交捕获方法，结合下一代测序以及新的计算生物信息学的实施，以精确地表征婴儿和老年小鼠各种器官中整个基因组中每个CpG岛上功能甲基化的存在或缺失。该项目将确定关键的全基因组、年龄相关和组织特定的表观遗传学变化，表明其表达或缺失对于适当的组织特定衰老是必要的基因。这些知识为定向研究提供了基础，以探索特定启动子或启动子组的正常甲基化中断如何改变正常人类衰老和组织特异性疾病的基因表达。

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.