Cellular aging and senescence of somatic cells and tissues occurs in all animals. In metazoans, aging consists of decreased regenerative capacity of renewable tissues, resulting from altered proliferation and differentiation of tissue stem and progenitor cell populations. In addition, certain model organisms, including the yeast, S. cerevisiae, have yielded remarkable insights into molecular pathways involved in aging and senescence. These include genomic changes such as telomere shortening, altered heterochromatic structure and function, and profound changes in gene expression. Our hypothesis is that epigenetic regulation is likely to be a key determinant underlying these age-associated changes in genomic structure and function. We will focus on two aspects of chromatin regulation: post-translational modifications of histone proteins, and chaperone-mediated assembly of histone variants into the nucleosomal scaffold. We will use several models: replicative lifespan-restriction of budding yeast mother cells and yeast senescence caused by telomere shortening, as well as senescence and differentiation of mammalian bone marrow-derived mesenchymal progenitor cells and aging of bone tissue. The projects are linked through collaborative studies of two major experimental focuses: the histone deacetylase Sir2 function in yeast aging and senescence, and the role of histone chaperones HIRA/ASF1a/UBN1 in regulating bone cell differentiation and senescence. The overarching theme is that aging, senescence and tissue differentiation are related by a strong epigenetic regulatory component. Our combined preliminary data support these aims and offer several unique and synergistic avenues to address major epigenetic questions of cellular and tissue aging. These key questions are (1) Is Sir2 activity, regulation, and localization directly involved in yeast replicative aging and senescence? Is histone H4 K16ac the key substrate of Sir2 related to its role in aging/senescence? (2) Can small molecules that alter Sir2 activity in vitro, alter the kinetics of aging/senescence in vivo? (3) What is the role of HIRA/ASF1a in regulation of chromatin structure during differentiation of bone marrow-derived mesenchymal progenitor cells? (4) What is the structure of the ASF1/HIRA/histone trimeric complex? What is the structure of HIRA in association with the chromatin protein Ubn1? How can these structure/function insights be used to enhance our understanding of cell senescence and tissue aging? Human disease is increasingly being linked to epigenetic pathways. Our project will provide new insights into the molecular basis of epigenetic regulation that drive eukaryotic aging, and will generate novel small molecule regulators of these pathways. Because epigenetic alterations are reversible, these studies have the potential to develop therapeutic agents and targets to alleviate debilitating aspects of aging and age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG031862-05
Application #
8235005
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (J2))
Program Officer
Guo, Max
Project Start
2008-03-15
Project End
2013-08-31
Budget Start
2012-03-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$1,729,395
Indirect Cost
$326,000
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Henderson, Alexander; Wu, Yuliang; Huang, Yu Chuan et al. (2014) Detection of G-quadruplex DNA in mammalian cells. Nucleic Acids Res 42:860-9
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
Mews, Philipp; Zee, Barry M; Liu, Sherry et al. (2014) Histone methylation has dynamics distinct from those of histone acetylation in cell cycle reentry from quiescence. Mol Cell Biol 34:3968-80
Plasschaert, Robert N; Vigneau, Sebastien; Tempera, Italo et al. (2014) CTCF binding site sequence differences are associated with unique regulatory and functional trends during embryonic stem cell differentiation. Nucleic Acids Res 42:7487
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
Brunet, Anne; Berger, Shelley L (2014) Epigenetics of aging and aging-related disease. J Gerontol A Biol Sci Med Sci 69 Suppl 1:S17-20
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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