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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG031862-10
Application #
9292232
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Guo, Max
Project Start
2008-03-15
Project End
2018-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Berson, Amit; Sartoris, Ashley; Nativio, Raffaella et al. (2017) TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr Biol 27:3579-3590.e6
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

Showing the most recent 10 out of 76 publications