Histone H4 lysine 16 acetylation regulates cellular lifespan

Weiwei Dang, Kristan K. Steffen, Rocco Perry, Jean A. Dorsey, F. Brad Johnson, Ali Shilatifard, Matt Kaeberlein, Brian K. Kennedy and Shelley L. Berger ()
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Weiwei Dang: Gene Expression and Regulation Program, The Wistar Institute Philadelphia, Pennsylvania 19104, USA
Kristan K. Steffen: Department of Biochemistry,
Rocco Perry: Gene Expression and Regulation Program, The Wistar Institute Philadelphia, Pennsylvania 19104, USA
Jean A. Dorsey: Gene Expression and Regulation Program, The Wistar Institute Philadelphia, Pennsylvania 19104, USA
F. Brad Johnson: Cell and Molecular Biology Group, Biomedical Graduate Studies and Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia 19104, Pennsylvania, USA
Ali Shilatifard: Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
Matt Kaeberlein: University of Washington Seattle, Washington 98195, USA
Brian K. Kennedy: Department of Biochemistry,
Shelley L. Berger: Gene Expression and Regulation Program, The Wistar Institute Philadelphia, Pennsylvania 19104, USA

Nature, 2009, vol. 459, issue 7248, 802-807

Abstract: Abstract Cells undergoing developmental processes are characterized by persistent non-genetic alterations in chromatin, termed epigenetic changes, represented by distinct patterns of DNA methylation and histone post-translational modifications. Sirtuins, a group of conserved NAD+-dependent deacetylases or ADP-ribosyltransferases, promote longevity in diverse organisms; however, their molecular mechanisms in ageing regulation remain poorly understood. Yeast Sir2, the first member of the family to be found, establishes and maintains chromatin silencing by removing histone H4 lysine 16 acetylation and bringing in other silencing proteins. Here we report an age-associated decrease in Sir2 protein abundance accompanied by an increase in H4 lysine 16 acetylation and loss of histones at specific subtelomeric regions in replicatively old yeast cells, which results in compromised transcriptional silencing at these loci. Antagonizing activities of Sir2 and Sas2, a histone acetyltransferase, regulate the replicative lifespan through histone H4 lysine 16 at subtelomeric regions. This pathway, distinct from existing ageing models for yeast, may represent an evolutionarily conserved function of sirtuins in regulation of replicative ageing by maintenance of intact telomeric chromatin.

Date: 2009
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DOI: 10.1038/nature08085

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