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:

Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing

Nature Genetics volume 32, pages 370–377 (2002)Cite this article

Abstract

Genes located in chromosomal regions near telomeres are transcriptionally silent, whereas those located in regions away from telomeres are not. Here we show that there is a gradient of acetylation of histone H4 at lysine 16 (H4–Lys16) along a yeast chromosome; this gradient ranges from a hypoacetylated state in regions near the telomere to a hyperacetylated state in more distant regions. The hyperacetylation is regulated by Sas2p, a member of the MYST-type family of histone acetylases, whereas hypoacetylation is under the control of Sir2p, a histone deacetylase. Loss of hyperacetylation is accompanied by an increase in localization of the telomere protein Sir3p and the inactivation of gene expression in telomere-distal regions. Thus, the Sas2p and Sir2p function in concert to regulate transcription in yeast, by acetylating and deacetylating H4–Lys16 in a mechanism that may be common to all eukaryotes.

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: Deletion of SAS2 causes a decrease in the overall acetylation of H4–Lys16 in vivo.
Figure 2: Chromosomal gradient of acetylation of H4–Lys16.
Figure 3: Deletion of SAS2 causes increased localization of Sir3p at a telomere-distal region.
Figure 4: Deletion of SAS2 causes gene repression in a region- and SIR3-dependent manner.
Figure 5: Model of the role of acetylation of H4–Lys16 in the localization of silencing proteins along chromosomes.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Gottschling, D.E., Aparicio, O.M., Billington, B.L. & Zakian, V.A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63, 751–762 (1990).

    Article  CAS  Google Scholar 

  2. Louis, E.J. The chromosome ends of Saccharomyces cerevisiae. Yeast 11, 1553–1573 (1995).

    Article  CAS  Google Scholar 

  3. Zakian, V.A. Structure, function, and replication of Saccharomyces cerevisiae telomeres. Annu. Rev. Genet. 30, 141–172 (1996).

    Article  CAS  Google Scholar 

  4. Vega-Palas, M.A., Venditti, S. & Di Mauro, E. Telomeric transcriptional silencing in a natural context. Nat. Genet. 15, 232–233 (1997).

    Article  CAS  Google Scholar 

  5. Loo, S. & Rine, J. Silencing and heritable domains of gene expression. Annu. Rev. Cell. Dev. Biol. 11, 519–548 (1995).

    Article  CAS  Google Scholar 

  6. Guarente, L. Diverse and dynamic functions of the Sir silencing complex. Nat. Genet. 23, 281–285 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Hecht, A., Laroche, T., Strahl-Bolsinger, S., Gasser, S.M. & Grunstein, M. Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell 80, 583–592 (1995).

    Article  CAS  Google Scholar 

  9. Martin, S.G., Laroche, T., Suka, N., Grunstein, M. & Gasser, S.M. Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast. Cell 97, 621–633 (1999).

    Article  CAS  Google Scholar 

  10. Mills, K.D., Sinclair, D.A. & Guarente, L. MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell 97, 609–620 (1999).

    Article  CAS  Google Scholar 

  11. Renauld, H. et al. Silent domains are assembled continuously from the telomere and are defined by promoter distance and strength, and by SIR3 dosage. Genes Dev. 7, 1133–1145 (1993).

    Article  CAS  Google Scholar 

  12. Wyrick, J.J. et al. Chromosomal landscape of nucleosome-dependent gene expression and silencing in yeast. Nature 402, 418–421 (1999).

    Article  CAS  Google Scholar 

  13. Hecht, A., Strahl-Bolsinger, S. & Grunstein, M. Spreading of transcriptional repressor SIR3 from telomeric heterochromatin. Nature 383, 92–96 (1996).

    Article  CAS  Google Scholar 

  14. Cockell, M. & Gasser, S.M. Nuclear compartments and gene regulation. Curr. Opin. Genet. Dev. 9, 199–205 (1999).

    Article  CAS  Google Scholar 

  15. Strahl, B.D. & Allis, C.D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  Google Scholar 

  16. Braunstein, M., Sobel, R.E., Allis, C.D., Turner, B.M. & Broach, J.R. Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Mol. Cell. Biol. 16, 4349–4356 (1996).

    Article  CAS  Google Scholar 

  17. 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 

  18. de Bruin, D., Kantrow, S.M., Liberatore, R.A. & Zakian, V.A. Telomere folding is required for the stable maintenance of telomere position effects in yeast. Mol. Cell. Biol. 20, 7991–8000 (2000).

    Article  CAS  Google Scholar 

  19. 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 

  20. 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 

  21. Johnson, L.M., Kayne, P.S., Kahn, E.S. & Grunstein, M. Genetic evidence for an interaction between SIR3 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 

  22. Aparicio, O.M., Billington, B.L. & Gottschling, D.E. Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Cell 66, 1279–1287 (1991).

    Article  CAS  Google Scholar 

  23. Carmen, A.A., Milne, L. & Grunstein, M. Acetylation of the yeast histone H4 N terminus regulates its binding to heterochromatin protein SIR3. J. Biol. Chem. 277, 4778–4781 (2002).

    Article  CAS  Google Scholar 

  24. 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 

  25. Smith, E.R. et al. ESA1 is a histone acetyltransferase that is essential for growth in yeast. Proc. Natl Acad. Sci. USA 95, 3561–3565 (1998).

    Article  CAS  Google Scholar 

  26. Kimura, A. & Horikoshi, M. Tip60 acetylates six lysines of a specific class in core histones in vitro. Genes Cells 3, 789–800 (1998).

    Article  CAS  Google Scholar 

  27. Hilfiker, A., Hilfiker-Kleiner, D., Pannuti, A. & Lucchesi, J.C. mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J. 16, 2054–2060 (1997).

    Article  CAS  Google Scholar 

  28. 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 

  29. Ehrenhofer-Murray, A.E., Rivier, D.H. & Rine, J. The role of Sas2, an acetyltransferase homologue of Saccharomyces cerevisiae, in silencing and ORC function. Genetics 145, 923–934 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Thompson, J.S., Ling, X. & Grunstein, M. Histone H3 amino terminus is required for telomeric and silent mating locus repression in yeast. Nature 369, 245–247 (1994).

    Article  CAS  Google Scholar 

  31. Meijsing, S.H. & Ehrenhofer-Murray, A.E. The silencing complex SAS-I links histone acetylation to the assembly of repressed chromatin by CAF-I and Asf1 in Saccharomyces cerevisiae. Genes. Dev. 15, 3169–3182 (2001).

    Article  CAS  Google Scholar 

  32. 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 

  33. Yamamoto, T. & Horikoshi, M. Novel substrate specificity of the histone acetyltransferase activity of HIV-1-Tat interactive protein Tip60. J. Biol. Chem. 272, 30595–30598 (1997).

    Article  CAS  Google Scholar 

  34. Osada, S. et al. The yeast SAS (something about silencing) protein complex contains a MYST-type putative acetyltransferase and functions with chromatin assembly factor ASF1. Genes Dev. 15, 3155–3168 (2001).

    Article  CAS  Google Scholar 

  35. Yan, Y., Barlev, N.A., Haley, R.H., Berger, S.L. & Marmorstein, R. Crystal structure of yeast Esa1 suggests a unified mechanism for catalysis and substrate binding by histone acetyltransferases. Mol. Cell 6, 1195–1205 (2000).

    Article  CAS  Google Scholar 

  36. Takechi, S. & Nakayama, T. Sas3 is a histone acetyltransferase and requires a zinc finger motif. Biochem. Biophys. Res. Commun. 266, 405–410 (1999).

    Article  CAS  Google Scholar 

  37. Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).

    Article  CAS  Google Scholar 

  38. Rundlett, S.E., Carmen, A.A., Suka, N., Turner, B.M. & Grunstein, M. Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3. Nature 392, 831–835 (1998).

    Article  CAS  Google Scholar 

  39. 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 

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

    Article  CAS  Google Scholar 

  41. Suka, N., Luo, K. & Grunstein, M. Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine 16 and spreading of heterochromatin. Nature Genet. 32 (2002); advance online publication, 15 October 2002 (doi:10.1038/ng1017).

  42. 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 

  43. Turner, B.M., Birley, A.J. & Lavender, J. Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei. Cell 69, 375–384 (1992).

    Article  CAS  Google Scholar 

  44. Kimura, A. & Horikoshi, M. How do histone acetyltransferases select lysine residues in core histones? FEBS Lett. 431, 131–133 (1998).

    Article  CAS  Google Scholar 

  45. Edmondson, D.G., Smith, M.M. & Roth, S.Y. Repression domain of the yeast global repressor Tup1 interacts directly with histones H3 and H4. Genes Dev. 10, 1247–1259 (1996).

    Article  CAS  Google Scholar 

  46. Dhalluin, C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496 (1999).

    Article  CAS  Google Scholar 

  47. 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 

  48. 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 

  49. 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 

  50. Knop, M. et al. Epitope tagging of yeast genes using a PCR-based strategy: more tags and improved practical routines. Yeast 15, 963–972 (1999).

    Article  CAS  Google Scholar 

  51. Wodicka, L., Dong, H., Mittmann, M., Ho, M.H. & Lockhart, D.J. Genome-wide expression monitoring in Saccharomyces cerevisiae. Nat. Biotechnol. 15, 1359–1367 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Gottschling, K. Nasmyth and J. Rine for plasmids and yeast strains; H. Araki, M. Grunstein, C. L. Peterson and K. Struhl for the protocols for the ChrIP assay; S. Harashima and Y. Ohya for tools and advice on yeast manipulation; K. Hasegawa, Y. Ikejiri, K. Matsubara, S. Okano, T. Sakuno and S. Yoshihara for technical assistance; and T. Suzuki, M. Yamaki and all members of our laboratory for discussions and comments on the manuscript. A.K. is a Research Fellow of the Japan Society for the Promotion of Science. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by Exploratory Research for Advanced Technology of the Japan Science and Technology Corporation.

Author information

Authors and Affiliations

  1. Horikoshi Gene Selector Project, Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, 5-9-6 Tokodai, Tsukuba, 300-2635, Ibaraki, Japan

    Akatsuki Kimura, Takashi Umehara & Masami Horikoshi

  2. Laboratory of Developmental Biology, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan

    Akatsuki Kimura & Masami Horikoshi

Authors
  1. Akatsuki Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Umehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masami Horikoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masami Horikoshi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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, 370–377 (2002). https://doi.org/10.1038/ng993

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng993

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