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关键部分，调节衰老过程中的异常可导致广泛的疾病和残疾，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知之甚少，这些过程如何在不同的器官系统之间的差异的知识是缺乏的。虽然先前的研究已经证明衰老与哺乳动物基因组中甲基化总体水平的普遍降低有关，但这些研究并没有关注哺乳动物生物体寿命期间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，在个体的一生中，暴露于明显不同水平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，这些基因表达是在给定组织内适当控制衰老过程所必需的。为了研究这些问题，我建议修改当前的杂交捕获方法，结合下一代测序沿着新的计算生物信息学的实施，以精确表征婴儿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，表明基因的表达或缺乏，是必要的适当组织特异性老化。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。 公共卫生相关性：健康老龄化是所有生命的一个重要部分，但人们对此知之甚少。然而，衰老不太可能是一个随机过程，贯穿哺乳动物有机体的整个生命。不同的器官以不同的速度发育和成熟，它们暴露于有毒代谢物和环境损伤的速度也不同。理所当然，调节正常衰老的过程中的异常会导致一系列疾病和残疾，如阿尔茨海默氏症、过早衰老、心力衰竭或癌症。调节基因表达的一种主要方法是通过启动子序列的甲基化。因此，更好地了解甲基化如何在哺乳动物的生命周期中调节不同生物体中的基因表达对于未来开发此类疾病的治疗方法至关重要。

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. PUBLIC HEALTH RELEVANCE: Healthy aging is a critical, but poorly understood, part of all life. However, aging is unlikely to be one stochastic process throughout the entire life of a mammalian organism. Different organs develop and mature at different rates, they have different rates of exposure to toxic metabolites and environmental insults. It stands to reason that abnormalities in the processes that regulate normal aging can result in a wide array of disease and disability such as Alzheimer's, premature aging, heart failure, or cancer. One primary method of regulating gene expression is through methylation of promoter sequences. Thus, a better understanding of how methylation regulates gene expression in different organism over a mammalian lifespan is essential for the future development of therapeutic treatments for such diseases.