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.

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 behaviour 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 #
2P01AG031862-06A1
Application #
8609442
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8 (01))
Program Officer
Guo, Max
Project Start
2008-03-15
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$1,791,874
Indirect Cost
$389,338
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
McCullough, Cheryl E; Marmorstein, Ronen (2016) Molecular Basis for Histone Acetyltransferase Regulation by Binding Partners, Associated Domains, and Autoacetylation. ACS Chem Biol 11:632-42
McCullough, C E; Marmorstein, R (2016) In Vitro Activity Assays for MYST Histone Acetyltransferases and Adaptation for High-Throughput Inhibitor Screening. Methods Enzymol 573:139-60
Rivera-Colón, Yadilette; Maguire, Andrew; Liszczak, Glen P et al. (2016) Molecular Basis for Cohesin Acetylation by Establishment of Sister Chromatid Cohesion N-Acetyltransferase ESCO1. J Biol Chem 291:26468-26477
Nelson, David M; Jaber-Hijazi, Farah; Cole, John J et al. (2016) Mapping H4K20me3 onto the chromatin landscape of senescent cells indicates a function in control of cell senescence and tumor suppression through preservation of genetic and epigenetic stability. Genome Biol 17:158
Ricketts, M Daniel; Marmorstein, Ronen (2016) A Molecular Prospective for HIRA Complex Assembly and H3.3-Specific Histone Chaperone Function. J Mol Biol :
Sen, Payel; Shah, Parisha P; Nativio, Raffaella et al. (2016) Epigenetic Mechanisms of Longevity and Aging. Cell 166:822-39
Capell, Brian C; Drake, Adam M; Zhu, Jiajun et al. (2016) MLL1 is essential for the senescence-associated secretory phenotype. Genes Dev 30:321-36
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
McCullough, Cheryl E; Song, Shufei; Shin, Michael H et al. (2016) Structural and Functional Role of Acetyltransferase hMOF K274 Autoacetylation. J Biol Chem 291:18190-8
Magin, Robert S; Liszczak, Glen P; Marmorstein, Ronen (2015) The molecular basis for histone H4- and H2A-specific amino-terminal acetylation by NatD. Structure 23:332-41

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