Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Histone H4 lysine 16 acetylation regulates cellular lifespan

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Collado, M., Blasco, M. A. & Serrano, M. Cellular senescence in cancer and aging. Cell 130, 223–233 (2007)

    Article  CAS  Google Scholar 

  2. Herbig, U. et al. Cellular senescence in aging primates. Science 311, 1257 (2006)

    Article  CAS  Google Scholar 

  3. Mair, W. & Dillin, A. Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77, 727–754 (2008)

    Article  CAS  Google Scholar 

  4. Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000)

    Article  ADS  CAS  Google Scholar 

  5. Fraga, M. F. & Esteller, M. Epigenetics and aging: the targets and the marks. Trends Genet. 23, 413–418 (2007)

    Article  CAS  Google Scholar 

  6. Oberdoerffer, P. & Sinclair, D. A. The role of nuclear architecture in genomic instability and ageing. Nature Rev. Mol. Cell Biol. 8, 692–702 (2007)

    Article  CAS  Google Scholar 

  7. Krishnamoorthy, T. et al. Phosphorylation of histone H4 Ser1 regulates sporulation in yeast and is conserved in fly and mouse spermatogenesis. Genes Dev. 20, 2580–2592 (2006)

    Article  CAS  Google Scholar 

  8. Longo, V. D. & Kennedy, B. K. Sirtuins in aging and age-related disease. Cell 126, 257–268 (2006)

    Article  CAS  Google Scholar 

  9. Moazed, D. Enzymatic activities of Sir2 and chromatin silencing. Curr. Opin. Cell Biol. 13, 232–238 (2001)

    Article  CAS  Google Scholar 

  10. Kimura, A., Umehara, T. & Horikoshi, M. Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing. Nature Genet. 32, 370–377 (2002)

    Article  Google Scholar 

  11. Suka, N., Luo, K. & Grunstein, M. Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin. Nature Genet. 32, 378–383 (2002)

    Article  CAS  Google Scholar 

  12. Sinclair, D. A. & Guarente, L. Extrachromosomal rDNA circles–a cause of aging in yeast. Cell 91, 1033–1042 (1997)

    Article  CAS  Google Scholar 

  13. Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580 (1999)

    Article  CAS  Google Scholar 

  14. Johzuka, K. & Horiuchi, T. Replication fork block protein, Fob1, acts as an rDNA region specific recombinator in S. cerevisiae . Genes Cells 7, 99–113 (2002)

    Article  CAS  Google Scholar 

  15. Defossez, P. A. et al. Elimination of replication block protein Fob1 extends the life span of yeast mother cells. Mol. Cell 3, 447–455 (1999)

    Article  CAS  Google Scholar 

  16. Johnson, F. B., Sinclair, D. A. & Guarente, L. Molecular biology of aging. Cell 96, 291–302 (1999)

    Article  CAS  Google Scholar 

  17. Laun, P. et al. Yeast mother cell-specific ageing, genetic (in)stability, and the somatic mutation theory of ageing. Nucleic Acids Res. 35, 7514–7526 (2007)

    Article  CAS  Google Scholar 

  18. Lin, Y. Y. et al. Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis. Cell 136, 1073–1084 (2009)

    Article  CAS  Google Scholar 

  19. Kouzarides, T. Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 19, 1176–1179 (2000)

    Article  CAS  Google Scholar 

  20. Glozak, M. A. & Seto, E. Histone deacetylases and cancer. Oncogene 26, 5420–5432 (2007)

    Article  CAS  Google Scholar 

  21. Haigis, M. C. & Guarente, L. P. Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913–2921 (2006)

    Article  CAS  Google Scholar 

  22. Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008)

    Article  ADS  CAS  Google Scholar 

  23. Saunders, L. R. & Verdin, E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 26, 5489–5504 (2007)

    Article  CAS  Google Scholar 

  24. Smeal, T. et al. Loss of transcriptional silencing causes sterility in old mother cells of S. cerevisiae . Cell 84, 633–642 (1996)

    Article  CAS  Google Scholar 

  25. Xu, F. et al. Sir2 deacetylates histone H3 lysine 56 to regulate telomeric heterochromatin structure in yeast. Mol. Cell 27, 890–900 (2007)

    Article  CAS  Google Scholar 

  26. Kaeberlein, M. & Powers, R. W. 3rd Sir2 and calorie restriction in yeast: a skeptical perspective. Ageing Res. Rev. 6, 128–140 (2007)

    Article  CAS  Google Scholar 

  27. Lesur, I. & Campbell, J. L. The transcriptome of prematurely aging yeast cells is similar to that of telomerase-deficient cells. Mol. Biol. Cell 15, 1297–1312 (2004)

    Article  CAS  Google Scholar 

  28. Rusche, L. N., Kirchmaier, A. L. & Rine, J. The establishment, inheritance, and function of silenced chromatin in Saccharomyces cerevisiae . Annu. Rev. Biochem. 72, 481–516 (2003)

    Article  CAS  Google Scholar 

  29. Pryde, F. E. & Louis, E. J. Limitations of silencing at native yeast telomeres. EMBO J. 18, 2538–2550 (1999)

    Article  CAS  Google Scholar 

  30. Robyr, D. et al. Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases. Cell 109, 437–446 (2002)

    Article  CAS  Google Scholar 

  31. Grubisha, O., Smith, B. C. & Denu, J. M. Small molecule regulation of Sir2 protein deacetylases. FEBS J. 272, 4607–4616 (2005)

    Article  CAS  Google Scholar 

  32. Shia, W. J., Li, B. & Workman, J. L. SAS-mediated acetylation of histone H4 Lys 16 is required for H2A.Z incorporation at subtelomeric regions in Saccharomyces cerevisiae . Genes Dev. 20, 2507–2512 (2006)

    Article  CAS  Google Scholar 

  33. Dion, M. F., Altschuler, S. J., Wu, L. F. & Rando, O. J. Genomic characterization reveals a simple histone H4 acetylation code. Proc. Natl Acad. Sci. USA 102, 5501–5506 (2005)

    Article  ADS  CAS  Google Scholar 

  34. Celic, I. et al. The sirtuins hst3 and Hst4p preserve genome integrity by controlling histone h3 lysine 56 deacetylation. Curr. Biol. 16, 1280–1289 (2006)

    Article  CAS  Google Scholar 

  35. Driscoll, R., Hudson, A. & Jackson, S. P. Yeast Rtt109 promotes genome stability by acetylating histone H3 on lysine 56. Science 315, 649–652 (2007)

    Article  ADS  CAS  Google Scholar 

  36. Han, J. et al. Rtt109 acetylates histone H3 lysine 56 and functions in DNA replication. Science 315, 653–655 (2007)

    Article  ADS  CAS  Google Scholar 

  37. Schneider, J. et al. Rtt109 is required for proper H3K56 acetylation: a chromatin mark associated with the elongating RNA polymerase II. J. Biol. Chem. 281, 37270–37274 (2006)

    Article  CAS  Google Scholar 

  38. Tsuchiya, M. et al. Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast. Aging Cell 5, 505–514 (2006)

    Article  CAS  Google Scholar 

  39. Huang, J. & Moazed, D. Association of the RENT complex with nontranscribed and coding regions of rDNA and a regional requirement for the replication fork block protein Fob1 in rDNA silencing. Genes Dev. 17, 2162–2176 (2003)

    Article  CAS  Google Scholar 

  40. Aguilaniu, H., Gustafsson, L., Rigoulet, M. & Nystrom, T. Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science 299, 1751–1753 (2003)

    Article  ADS  CAS  Google Scholar 

  41. Blasco, M. A. The epigenetic regulation of mammalian telomeres. Nature Rev. Genet. 8, 299–309 (2007)

    Article  CAS  Google Scholar 

  42. Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009)

    Article  CAS  Google Scholar 

  43. Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006)

    Article  CAS  Google Scholar 

  44. Park, P. U., McVey, M. & Guarente, L. Separation of mother and daughter cells. Methods Enzymol. 351, 468–477 (2002)

    Article  Google Scholar 

  45. Wyce, A. et al. H2B ubiquitylation acts as a barrier to Ctk1 nucleosomal recruitment prior to removal by Ubp8 within a SAGA-related complex. Mol. Cell 27, 275–288 (2007)

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shelley L. Berger.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12 with Legends and Supplementary Tables 1-5. (PDF 934 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08085

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing