The role of global epigenetic changes in the aging process and age-related degenerative disorders is unknown. This proposal is based on the working hypothesis that specific cell types and tissues drive the aging process through global changes in the epigenome. To explore this hypothesis, we have conceived a novel system to address the methodological shortcomings that currently preclude cell-type-specific epigenetic analysis in complex tissues. The planned new approach, which we term Chromatin Isolation and Chromatin Immunoprecipitation (CI- ChIP), will involve transgenic expression of a tagged core histone in cells of interest using a cell type-specific promoter. The tagged histone would then be incorporated into the chromatin of the cells of interest, permitting the isolation of chromatin from specific cells in any animal model or complex tissue. We intend to use the nematode worm, Caenorhabditis elegans, to develop CI- ChIP. The genetic tractability and aging biology of the worm offers many advantages. Development of CI-ChIP would have immediate benefits for the study of gene expression and the epigenetics of aging in C. elegans. Furthermore, changes in gene expression during aging and under conditions that extend longevity could be measured at the tissue level for the first time. This will enable investigation of the molecular basis of differential rates of aging and the contribution of each of the major cell types in the worm. To explore the role of epigenetic changes in mammalian aging, CI-ChIP will be applied to transgenic mice expressing tagged histones targeted to tissues with pronounced age-related pathology, including the brain, heart, skeletal muscle, vasculature and pancreas. This would allow for global epigenetic analysis at cell type-specific resolution in any mouse model of disease, development or physiology. Finally, it is conceivable that CI-ChIP might lead to technology for predicting individuals at risk for age- related degenerative disorde
Why some people age more rapidly than others and develop age-related disorders, such as diabetes and Alzheimers disease, is not well understood. We propose that epigenetic changes, modifications of genes acquired during life, play a central role. A major obstacle to exploring this mechanism, however, is the variety of different cell types present in any complex tissue, such as the brain or heart, and in any model system, such as worms, flies or mice. We have conceived of a novel approach that may solve this problem, providing an unprecedented view of the workings of the genome during aging in health and disease.
|Lu, Tao; Aron, Liviu; Zullo, Joseph et al. (2014) REST and stress resistance in ageing and Alzheimer's disease. Nature 507:448-54|
|Gabuzda, Dana; Yankner, Bruce A (2013) Physiology: Inflammation links ageing to the brain. Nature 497:197-8|