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, yeas 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 behavior 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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|Bonini, Nancy M; Berger, Shelley L (2017) The Sustained Impact of Model Organisms-in Genetics and Epigenetics. Genetics 205:1-4|
|Mews, Philipp; Donahue, Greg; Drake, Adam M et al. (2017) Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 546:381-386|
|Ricketts, M Daniel; Marmorstein, Ronen (2017) A Molecular Prospective for HIRA Complex Assembly and H3.3-Specific Histone Chaperone Function. J Mol Biol 429:1924-1933|
|Simithy, Johayra; Sidoli, Simone; Yuan, Zuo-Fei et al. (2017) Characterization of histone acylations links chromatin modifications with metabolism. Nat Commun 8:1141|
|Yang, Ting-Lin B; Chen, Qijun; Deng, Jennifer T et al. (2017) Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche. Nat Commun 8:14766|
|Feng, Zijie; Wang, Lei; Sun, Yanmei et al. (2017) Menin and Daxx Interact to Suppress Neuroendocrine Tumors through Epigenetic Control of the Membrane Metallo-Endopeptidase. Cancer Res 77:401-411|
|Vizioli, Maria Grazia; Adams, Peter D (2016) Senescence Can Be BETter without the SASP? Cancer Discov 6:576-8|
|Sen, Payel; Shah, Parisha P; Nativio, Raffaella et al. (2016) Epigenetic Mechanisms of Longevity and Aging. Cell 166:822-839|
|Pchelintsev, Nikolay A; Adams, Peter D; Nelson, David M (2016) Critical Parameters for Efficient Sonication and Improved Chromatin Immunoprecipitation of High Molecular Weight Proteins. PLoS One 11:e0148023|
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