The budding yeast S. cerevisiae provides a surprising and remarkably useful model for longevity studies, because certain genetic and metabolic pathways regulating aging in yeast are evolutionarily conserved in metazoans, even in humans. In particular yeast provides a tractable genetic model for replicative aging, since yeast cells divide a certain number of times and then cease to replicate. A number of observations suggest that alterations in chromatin structure, including changes in histone covalent post-translational modifications, occur as yeast age. For example, experimental manipulation of Sir2 levels, a deacetylase that targets histones, changes the kinetics of aging - loss of Sir2 causes more rapid aging and over-expression of Sir2 causes delayed aging. However, whether chromatin changes are an important aspect of agingjs not well understood. Our hypothesis is that alterations of histone post-translational modifications and changes in chromatin structure cause decompaction of heterochromatic regions of the genome during yeast replicative aging and may directly contribute to the aging phenotype. We further hypothesize that the chromatin changes are epigenetic, in that they are a stable, inherited attribute of the aging yeast cell. In the proposed research we will test these hypotheses via several specific aims. (1) Our first goal is to determine whether Sir2 deacetylation of histone H416ac (a well-characterized substrate of Sir2) has a central physiological role to antagonize yeast aging. We will determine whether deacetylation of H4K16ac maintains compaction of heterochromatic regions in young yeast, and will investigate the mechanism of gradual decompaction as a key change in chromatin underlying aging. (2) Second, we will examine whether regulation of Sir2 is a critical aspect of aging. Sir2 function is reduced during yeast and metazoan aging, however the mechanistic basis of this has not been elucidated. We will determine whether the activity, regulation, and localization of Sir2 are altered, and if small molecule effectors can regulate Sir2 function during aging. (3) Finally, we will investigate a wider role of chromatin changes during aging including additional histone modifications, nucleosome remodeling, and altered histone composition. We will collaborate extensively with the other Projects within this Program. We will collaborate with Project 1 (R. Marmorstein) to examine physiological and small molecule activators and inhibitors of Sir2 during aging. We will collaborate with Project 3 (B. Johnson) to test conservation of Sir2 mechanisms in yeast replicative aging and replicative senescence in the telomerase deficiency model. We will collaborate with Project 4 (P. Adams) to investigate possible conservation in yeast of histone chaperone protein complexes relevant to heterochromatic foci that occur in the mammalian bone senescence model.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG031862-05
Application #
8377710
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5)
Project Start
Project End
2013-08-31
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$383,503
Indirect Cost
$63,764
Name
University of Pennsylvania
Department
Type
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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