Epigenetics is defined as heritable changes in genomic function and phenotype that do not involve alteration to DNA sequence. This higher level control of genome function is embodied in chromatin, a composite of nucleosomes (DNA and histones), as well as other non-histone proteins. Human disease is increasingly being linked to epigenetic and chromatin changes. The central hypothesis of this Program Project is that chromatin, as an inherently dynamic structure, is prone to age-associated degeneration, but that this degeneration is also countered by protective processes. This Program Project studies these age-associated chcomatin changes as they occur in the context of cell senescence, an irreversible proliferation arrest of damaged cells that contributes to tissue aging. Our studies from the first cycle of funding confirmed the previously suspected role for epigenetics as a critical determinant of aging and longevity. As a cross-disciplinary and highly collaborative team (46 manuscripts to date [published or submitted] in the 2008-2013 funding cycle, of which 19 are collaborative), we will continue to employ biochemistry, structural biology, cell biology, yeast genetics, and state-of-the-art epigenomic technologies in yeast and human cells to elucidate the role of epigenetics in aging and senescence. In particular, we will define degenerative and protective changes to chromatin, and the molecular mechanisms underlying them. The relevance of these studies for aging will be tested by reference to young and old human tissues and in mouse models, assessing phenotypes of aging. Moreover, based on our findings from the first cycle of funding, we have already initiated efforts to leverage our mechanistic insights into lead compounds for novel therapies to promote healthy aging. Our ultimate goal is to understand the balance of processes that culminate in age-associated chromatin dysfunction, so that we can devise strategies to manipulate the balance to promote healthy aging.
We hypothesize that aging results, in part, from progressive degeneration of nuclear organization;at the same time, there are other cell-intrinsic processes which counter this degeneration. Our goal is to understand these processes, so that we can intervene, with changes to behaviour and diet or use of drug therapies, to promote healthy aging. Drug discovery efforts are in progress based on our findings to date.
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|Dong, Dawei W; Pereira, Filipe; Barrett, Steven P et al. (2014) Association of G-quadruplex forming sequences with human mtDNA deletion breakpoints. BMC Genomics 15:677|
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|Johnson, Jay E; Johnson, F Brad (2014) Methionine restriction activates the retrograde response and confers both stress tolerance and lifespan extension to yeast, mouse and human cells. PLoS One 9:e97729|
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|Marmorstein, Ronen; Zhou, Ming-Ming (2014) Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol 6:a018762|
|Tsai, Kevin; Chan, Lilian; Gibeault, Rebecca et al. (2014) Viral reprogramming of the Daxx histone H3.3 chaperone during early Epstein-Barr virus infection. J Virol 88:14350-63|
|Dang, Weiwei; Sutphin, George L; Dorsey, Jean A et al. (2014) Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response. Cell Metab 19:952-66|
|Ivanov, Andre; Pawlikowski, Jeff; Manoharan, Indrani et al. (2013) Lysosome-mediated processing of chromatin in senescence. J Cell Biol 202:129-43|
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