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Histone H4 lysine 16 acetylation regulates cellular lifespan

Nature volume 459, pages 802–807 (2009)Cite this article

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.

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Figure 1: Chromatin and Sir2 levels change in old cells.
Figure 2: The X core elements of telomeres show silencing defects in old cells.
Figure 3: Sas2 antagonizes Sir2 in regulating lifespan and H4K16 acetylation.
Figure 4: Histone H4K16 and H3K56 mutations affect replicative lifespan through distinct mechanisms.
Figure 5: H4K16 is involved in a Sir2-regulated ageing pathway associated with telomere chromatin.

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Acknowledgements

We thank E. Louis for providing strains for the telomere silencing assay, and members of the Kennedy and Kaeberlein labs who participated in lifespan-determination studies. This work was funded by US National Institutes of Health grants (S.L.B. and B.K.K.), and an American Federation for Aging Research Julie Martin Mid-Career Award in Aging Research (B.K.K.). M.K. is an Ellison Medical Foundation New Scholar in Aging.

Author Contributions Project planning was performed by W.D., F.B.J., A.S., B.K.K. and S.L.B; experimental work by W.D., K.K.S., R.P. and J.A.D.; data analysis by W.D.,K.K.S., F.B.J., M.K., B.K.K. and S.L.B.; and manuscript composition by W.D., F.B.J., M.K., B.K.K. and S.L.B.

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Authors and Affiliations

  1. Gene Expression and Regulation Program, The Wistar Institute Philadelphia, Pennsylvania 19104, USA ,

    Weiwei Dang, Rocco Perry, Jean A. Dorsey & Shelley L. Berger

  2. Department of Biochemistry,,

    Kristan K. Steffen & Brian K. Kennedy

  3. Department of Pathology, University of Washington Seattle, Washington 98195, USA,

    Matt Kaeberlein

  4. Department of Pathology and Laboratory Medicine, Cell and Molecular Biology Group, Biomedical Graduate Studies and Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia 19104, Pennsylvania, USA,

    F. Brad Johnson

  5. Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA ,

    Ali Shilatifard

  6. Department of Cell & Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA,

    Shelley L. Berger

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  1. Weiwei Dang
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Correspondence to Shelley L. Berger.

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Dang, W., Steffen, K., Perry, R. et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807 (2009). https://doi.org/10.1038/nature08085

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