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.
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.
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