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.

  • Article
  • Published:

Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin

Nature Genetics volume 32, pages 378–383 (2002)Cite this article

Abstract

The Sir3 protein helps form telomeric heterochromatin by interacting with hypoacetylated histone H4 lysine 16 (H4–Lys16). The molecular nature of the heterochromatin boundary is still unknown. Here we show that the MYST-like acetyltransferase Sas2p is required for the acetylation (Ac) of H4–Lys16 in euchromatin. In a sas2Δ strain or a phenocopy Lys16Arg mutant, Sir3p spreads from roughly 3 kb to roughly 15 kb, causing hypoacetylation and repression of adjacent chromatin. We also found that disruption of Sir3p binding in a deacetylase-deficient Sir 2Δ strain can be suppressed by sas2Δ. These data indicate that opposing effects of Sir2p and Sas2p on acetylation of H4–Lys16 maintain the boundary at telomeric heterochromatin.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Esa1p and Sas2p are required redundantly for the acetylation on H4–Lys16 in chromatin surrounding the INO1 promoter.
Figure 2: The sas2Δ mutation resulted in less acetylation on all H4 sites at sub-telomeric chromatin.
Figure 3: H4–Lys16Arg but not H4–Lys12Arg resulted in less acetylation on other H4 and H3 sites at sub-telomeric heterochromatin.
Figure 4: Acetylation on H4–Lys16 affects spreading of Sir protein at sub-telomeric regions.
Figure 5: Both lower acetylation at 7.6 kb and lower expression of sub-telomeric genes in sas2Δ or H4–Lys16Arg strains are dependent on Sir3p.
Figure 6: Sas2p and acetylation on histone H4–Lys16 are proposed to generate a boundary for the spreading of telomeric heterochromatin.

Similar content being viewed by others

References

  1. Braunstein, M., Rose, A.B., Holmes, S.G., Allis, C.D. & Broach, J.R. Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 7, 592–604 (1993).

    Article  CAS  Google Scholar 

  2. Suka, N., Suka, Y., Carmen, A.A., Wu, J. & Grunstein, M. Highly specific antibodies determine histone acetylation site usage in yeast heterochromatin and euchromatin. Mol. Cell 8, 473–479 (2001).

    Article  CAS  Google Scholar 

  3. Moretti, P., Freeman, K., Coodly, L. & Shore, D. Evidence that a complex of Sir proteins interacts with the silencer and telomere-binding protein RAP1. Genes Dev. 8, 2257–2269 (1994).

    Article  CAS  Google Scholar 

  4. Grunstein, M. Molecular model for telomeric heterochromatin in yeast. Curr. Opin. Cell Biol. 9, 383–387 (1997).

    Article  CAS  Google Scholar 

  5. Johnson, L.M., Kayne, P.S., Kahn, E.S. & Grunstein, M. Genetic evidence for an interaction between Sir3p and histone H4 in the repression of the silent mating loci in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 87, 6286–6290 (1990).

    Article  CAS  Google Scholar 

  6. Megee, P.C., Morgan, B.A., Mittman, B.A. & Smith, M.M. Genetic analysis of histone H4: essential role of lysines subject to reversible acetylation. Science 247, 841–845 (1990).

    Article  CAS  Google Scholar 

  7. Carmen, A.A., Milne, L. & Grunstein, M. Acetylation on the yeast histone H4 N terminus regulates its binding to heterochromatin protein Sir3p. J. Biol. Chem. 277, 4778–4781 (2002).

    Article  CAS  Google Scholar 

  8. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    Article  CAS  Google Scholar 

  9. Bannister, A.J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).

    Article  CAS  Google Scholar 

  10. Litt, M.D., Simpson, M., Gaszner, M., Allis, C.D. & Felsenfeld, G. Correlation between histone lysine methylation and developmental changes at the chicken β-globin locus. Science 293, 2453–2455 (2001).

    Article  CAS  Google Scholar 

  11. Nakayama, J., Rice, J.C., Strahl, B.D., Allis, C.D. & Grewal, S.I. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292, 110–113 (2001).

    Article  CAS  Google Scholar 

  12. Strahl, B.D., Ohba, R., Cook, R.G. & Allis, C.D. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena. Proc. Natl Acad. Sci. USA 96, 14967–14972 (1999).

    Article  CAS  Google Scholar 

  13. Strahl, B.D. et al. Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol. Cell. Biol. 22, 1298–1306 (2002).

    Article  CAS  Google Scholar 

  14. Donze, D. & Kamakaka, R.T. RNA polymerase III and RNA polymerase II promoter complexes are heterochromatin barriers in Saccharomyces cerevisiae. EMBO J. 20, 520–531 (2001).

    Article  CAS  Google Scholar 

  15. Clarke, D.J., O'Neill, L.P. & Turner, B.M. Selective use of H4 acetylation sites in the yeast Saccharomyces cerevisiae. Biochem J. 294, 557–561 (1993).

    Article  CAS  Google Scholar 

  16. Grunstein, M. Yeast heterochromatin: regulation of its assembly and inheritance by histones. Cell 93, 325–328 (1998).

    Article  CAS  Google Scholar 

  17. Reifsnyder, C., Lowell, J., Clarke, A. & Pillus, L. Yeast SAS silencing genes and human genes associated with AML and HIV-1 Tat interactions are homologous with acetyltransferases. Nat. Genet. 14, 42–49 (1996).

    Article  CAS  Google Scholar 

  18. Akhtar, A. & Becker, P.B. Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol. Cell 5, 367–375 (2000).

    Article  CAS  Google Scholar 

  19. Smith, E.R. et al. The Drosophila MSL complex acetylates histone H4 at lysine 16, a chromatin modification linked to dosage compensation. Mol. Cell. Biol. 20, 312–318 (2000).

    Article  CAS  Google Scholar 

  20. Imai, S., Armstrong, C.M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

    Article  CAS  Google Scholar 

  21. Clarke, A.S., Lowell, J.E., Jacobson, S.J. & Pillus, L. Esa1p is an essential histone acetyltransferase required for cell cycle progression. Mol. Cell. Biol. 19, 2515–2526 (1999).

    Article  CAS  Google Scholar 

  22. Renauld, H. et al. Silent domains are assembled continuously from the telomere and are defined by promoter distance and strength, and by Sir3p dosage. Genes Dev. 7, 1133–1345 (1993).

    Article  CAS  Google Scholar 

  23. Hecht, A., Strahl-Bolsinger, S. & Grunstein, M. Spreading of transcriptional repressor Sir3p from telomeric heterochromatin. Nature 383, 92–96 (1996).

    Article  CAS  Google Scholar 

  24. Strahl-Bolsinger, S., Hecht, A., Luo, K. & Grunstein, M. Sir2 and Sir4 interactions differ in core and extended telomeric heterochromatin in yeast. Genes Dev. 11, 83–93 (1997).

    Article  CAS  Google Scholar 

  25. Johnson, L.M., Fisher-Adams, G. & Grunstein, M. Identification of a non-basic domain in the histone H4 N-terminus required for repression of the yeast silent mating loci. EMBO J. 11, 2201–2209 (1992).

    Article  CAS  Google Scholar 

  26. Hecht, A., Laroche, T., Strahl-Bolsinger, S., Gasser, S.M. & Grunstein, M. Histone H3 and H4 N-termini interact with Sir3p and Sir4p proteins: a molecular model for the formation of heterochromatin in yeast. Cell 80, 583–592 (1995).

    Article  CAS  Google Scholar 

  27. Kimura, A., Umehara, T. & Horikoshi, M. Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing. Nat. Genet. 32 (2002); advance online publication, 15 October 2002 (doi:10.10138/993).

  28. Fourel, G., Revardel, E., Koering, C.E. & Gilson, E. Cohabitation of insulators and silencing elements in yeast subtelomeric regions. EMBO J. 18, 2522–2537 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Gu, W., Wei, X., Pannuti, A. & Lucchesi, J.C. Targeting the chromatin-remodeling MSL complex of Drosophila to its sites of action on the X chromosome requires both acetyl transferase and ATPase activities. EMBO J. 19, 5202–5211 (2000).

    Article  CAS  Google Scholar 

  31. Wach, A. et al. PCR-based gene targeting in Saccharomyces cerevisiae. Method in Microbiology Vol. 26 (eds Brown, P.D.P. & Tuite, M.F.) 67–81 (Academic, London, 1998).

    Google Scholar 

  32. Vogelauer, M., Wu, J., Suka, N. & Grunstein, M. Global histone acetylation and deacetylation in yeast. Nature 408, 495–498 (2000).

    Article  CAS  Google Scholar 

  33. Brown, A.J.P., Furness, L.M. & Bailey, D. Transcript analysis. Method in Microbiology Vol. 26 (eds Brown, P.D.P. & Tuite, M.F.) 119–139 (Academic, London, 1998).

    Google Scholar 

Download references

Acknowledgements

We thank L. Pillus for the esa1ts strain and the members of M.G.'s laboratory for critical comments and discussions throughout this work. This work was supported by a Public Health Service grant from the U.S. National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Biological Chemistry, UCLA School of Medicine and the Molecular Biology Institute, Boyer Hall, University of California, Los Angeles, 90095, California, USA

    Noriyuki Suka, Kunheng Luo & Michael Grunstein

Authors
  1. Noriyuki Suka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kunheng Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Grunstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Grunstein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Suka, N., Luo, K. & Grunstein, M. Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin. Nat Genet 32, 378–383 (2002). https://doi.org/10.1038/ng1017

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1017

This article is cited by

Search

Advanced 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