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.

  • Analysis
  • Published:

A genome-wide analysis in Saccharomyces cerevisiae demonstrates the influence of chromatin modifiers on transcription

Nature Genetics volume 39, pages 303–309 (2007)Cite this article

Abstract

Chromatin structure is important in transcription regulation. Many factors influencing chromatin structure have been identified, but the transcriptional programs in which they participate are still poorly understood. Chromatin modifiers participate in transcriptional control together with DNA-bound transcription factors. High-throughput experimental methods allow the genome-wide identification of binding sites for transcription factors as well as quantification of gene expression under various environmental and genetic conditions. We have developed a new methodology that uses the vast amount of available data to dissect the contribution of chromatin structure to transcription. We measure and characterize the dependence of transcription factor function on specific chromatin modifiers. We apply our methodology to S. cerevisiae, using a compendium of 170 gene expression profiles of strains defective for chromatin modifiers, taken from 26 different studies. Our method succeeds in identifying known intricate genetic interactions between chromatin modifiers and transcription factors and uncovers many previously unknown genetic interactions, giving the first genome-wide picture of the contribution of chromatin structure to transcription in a eukaryote.

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: A model for chromatin modifier-mediated transcription.
Figure 2: The chromatin modifier gene expression compendium.
Figure 3: Distribution of expression values for the Ume6 cohort in various chromatin modifier knockout experiments.
Figure 4: Overlap in altered cohort genes.
Figure 5: Distribution of expression values for the Yap6 cohort in various chromatin modifier knockout experiments.

Similar content being viewed by others

References

  1. Harbison, C.T. et al. Transcriptional regulatory code of a eukaryotic genome. Nature 431, 99–104 (2004).

    Article  CAS  Google Scholar 

  2. Kurdistani, S.K. & Grunstein, M. Histone acetylation and deacetylation in yeast. Nat. Rev. Mol. Cell Biol. 4, 276–284 (2003).

    Article  CAS  Google Scholar 

  3. Tsukiyama, T. The in vivo functions of ATP-dependent chromatin-remodelling factors. Nat. Rev. Mol. Cell Biol. 3, 422–429 (2002).

    Article  CAS  Google Scholar 

  4. Eberharter, A. & Becker, P.B. Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep. 3, 224–229 (2002).

    Article  CAS  Google Scholar 

  5. Kadosh, D. & Struhl, K. Repression by Ume6 involves recruitment of a complex containing Sin3 corepressor and Rpd3 histone deacetylase to target promoters. Cell 89, 365–371 (1997).

    Article  CAS  Google Scholar 

  6. Swanson, M.J. et al. A multiplicity of coactivators is required by Gcn4p at individual promoters in vivo. Mol. Cell. Biol. 23, 2800–2820 (2003).

    Article  CAS  Google Scholar 

  7. Lee, T.I. et al. Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298, 799–804 (2002).

    Article  CAS  Google Scholar 

  8. Stephens, M.A. Use of the Kolmogorov-Smirnov, Cramer-von Mises and related statistics without extensive tables. J. R. Stat. Soc. [Ser A] 32, 115–122 (1970).

    Google Scholar 

  9. Fazzio, T.G. et al. Widespread collaboration of Isw2 and Sin3-Rpd3 chromatin remodeling complexes in transcriptional repression. Mol. Cell. Biol. 21, 6450–6460 (2001).

    Article  CAS  Google Scholar 

  10. Goldmark, J.P., Fazzio, T.G., Estep, P.W., Church, G.M. & Tsukiyama, T. The Isw2 chromatin remodeling complex represses early meiotic genes upon recruitment by Ume6p. Cell 103, 423–433 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Rubin-Bejerano, I., Mandel, S., Robzyk, K. & Kassir, Y. Induction of meiosis in Saccharomyces cerevisiae depends on conversion of the transcriptional represssor Ume6 to a positive regulator by its regulated association with the transcriptional activator Ime1. Mol. Cell. Biol. 16, 2518–2526 (1996).

    Article  CAS  Google Scholar 

  13. Sabet, N., Volo, S., Yu, C., Madigan, J.P. & Morse, R.H. Genome-wide analysis of the relationship between transcriptional regulation by Rpd3p and the histone H3 and H4 amino termini in budding yeast. Mol. Cell. Biol. 24, 8823–8833 (2004).

    Article  CAS  Google Scholar 

  14. Clapier, C.R., Langst, G., Corona, D.F., Becker, P.B. & Nightingale, K.P. Critical role for the histone H4 N terminus in nucleosome remodeling by ISWI. Mol. Cell. Biol. 21, 875–883 (2001).

    Article  CAS  Google Scholar 

  15. Fazzio, T.G., Gelbart, M.E. & Tsukiyama, T. Two distinct mechanisms of chromatin interaction by the Isw2 chromatin remodeling complex in vivo. Mol. Cell. Biol. 25, 9165–9174 (2005).

    Article  CAS  Google Scholar 

  16. Hinnebusch, A.G. Translational regulation of GCN4 and the general amino acid control of yeast. Annu. Rev. Microbiol. 59, 407–450 (2005).

    Article  CAS  Google Scholar 

  17. Kuo, M.H., vom Baur, E., Struhl, K. & Allis, C.D. Gcn4 activator targets Gcn5 histone acetyltransferase to specific promoters independently of transcription. Mol. Cell 6, 1309–1320 (2000).

    Article  CAS  Google Scholar 

  18. Natarajan, K., Jackson, B.M., Zhou, H., Winston, F. & Hinnebusch, A.G. Transcriptional activation by Gcn4p involves independent interactions with the SWI/SNF complex and the SRB/mediator. Mol. Cell 4, 657–664 (1999).

    Article  CAS  Google Scholar 

  19. Hughes, T.R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109–126 (2000).

    Article  CAS  Google Scholar 

  20. Natarajan, K. et al. Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast. Mol. Cell. Biol. 21, 4347–4368 (2001).

    Article  CAS  Google Scholar 

  21. Keogh, M.C. et al. Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 123, 593–605 (2005).

    Article  CAS  Google Scholar 

  22. Mendizabal, I., Rios, G., Mulet, J.M., Serrano, R. & de Larrinoa, I.F. Yeast putative transcription factors involved in salt tolerance. FEBS Lett. 425, 323–328 (1998).

    Article  CAS  Google Scholar 

  23. Wu, J., Suka, N., Carlson, M. & Grunstein, M. TUP1 utilizes histone H3/H2B-specific HDA1 deacetylase to repress gene activity in yeast. Mol. Cell 7, 117–126 (2001).

    Article  CAS  Google Scholar 

  24. Smith, R.L. & Johnson, A.D. Turning genes off by Ssn6-Tup1: a conserved system of transcriptional repression in eukaryotes. Trends Biochem. Sci. 25, 325–330 (2000).

    Article  CAS  Google Scholar 

  25. Santos-Rosa, H., Bannister, A.J., Dehe, P.M., Geli, V. & Kouzarides, T. Methylation of H3 lysine 4 at euchromatin promotes Sir3p association with heterochromatin. J. Biol. Chem. 279, 47506–47512 (2004).

    Article  CAS  Google Scholar 

  26. Grant, P.A. et al. Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Genes Dev. 11, 1640–1650 (1997).

    Article  CAS  Google Scholar 

  27. Huisinga, K.L. & Pugh, B.F. A genome-wide housekeeping role for TFIID and a highly regulated stress-related role for SAGA in Saccharomyces cerevisiae. Mol. Cell 13, 573–585 (2004).

    Article  CAS  Google Scholar 

  28. Bhaumik, S.R. & Green, M.R. Differential requirement of SAGA components for recruitment of TATA-box-binding protein to promoters in vivo. Mol. Cell. Biol. 22, 7365–7371 (2002).

    Article  CAS  Google Scholar 

  29. Sterner, D.E., Belotserkovskaya, R. & Berger, S.L. SALSA, a variant of yeast SAGA, contains truncated Spt7, which correlates with activated transcription. Proc. Natl. Acad. Sci. USA 99, 11622–11627 (2002).

    Article  CAS  Google Scholar 

  30. Belotserkovskaya, R. et al. Inhibition of TATA-binding protein function by SAGA subunits Spt3 and Spt8 at Gcn4-activated promoters. Mol. Cell. Biol. 20, 634–647 (2000).

    Article  CAS  Google Scholar 

  31. Pugh, B.F. Control of gene expression through regulation of the TATA-binding protein. Gene 255, 1–14 (2000).

    Article  CAS  Google Scholar 

  32. Chitikila, C., Huisinga, K.L., Irvin, J.D., Basehoar, A.D. & Pugh, B.F. Interplay of TBP inhibitors in global transcriptional control. Mol. Cell 10, 871–882 (2002).

    Article  CAS  Google Scholar 

  33. Zhang, L. & Hach, A. Molecular mechanism of heme signaling in yeast: the transcriptional activator Hap1 serves as the key mediator. Cell. Mol. Life Sci. 56, 415–426 (1999).

    Article  CAS  Google Scholar 

  34. Raitt, D.C. et al. The Skn7 response regulator of Saccharomyces cerevisiae interacts with Hsf1 in vivo and is required for the induction of heat shock genes by oxidative stress. Mol. Biol. Cell 11, 2335–2347 (2000).

    Article  CAS  Google Scholar 

  35. Bahler, J. Cell-cycle control of gene expression in budding and fission yeast. Annu. Rev. Genet. 39, 69–94 (2005).

    Article  CAS  Google Scholar 

  36. Basehoar, A.D., Zanton, S.J. & Pugh, B.F. Identification and distinct regulation of yeast TATA box-containing genes. Cell 116, 699–709 (2004).

    Article  CAS  Google Scholar 

  37. Hartemink, A.J., Gifford, D.K., Jaakkola, T.S. & Young, R.A. Combining location and expression data for principled discovery of genetic regulatory network models. Pac. Symp. Biocomput., 437–449 (2002).

  38. Gardner, T.S., di Bernardo, D., Lorenz, D. & Collins, J.J. Inferring genetic networks and identifying compound mode of action via expression profiling. Science 301, 102–105 (2003).

    Article  CAS  Google Scholar 

  39. Segal, E. et al. Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat. Genet. 34, 166–176 (2003).

    Article  CAS  Google Scholar 

  40. Workman, C.T. et al. A systems approach to mapping DNA damage response pathways. Science 312, 1054–1059 (2006).

    Article  CAS  Google Scholar 

  41. Khorasanizadeh, S. The nucleosome: from genomic organization to genomic regulation. Cell 116, 259–272 (2004).

    Article  CAS  Google Scholar 

  42. Tanay, A., Steinfeld, I., Kupiec, M. & Shamir, R. Integrative analysis of genome-wide experiments in the context of a large high-throughput data compendium. Mol. Syst. Biol. 2005, 2005.0002 (2005).

  43. Harris, M.A. et al. The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res. 32, D258–D261 (2004).

    Article  CAS  Google Scholar 

  44. Shamir, R. et al. EXPANDER–an integrative program suite for microarray data analysis. BMC Bioinformatics 6, 232 (2005).

    Article  Google Scholar 

  45. Bernstein, B.E. et al. Methylation of histone H3 Lys 4 in coding regions of active genes. Proc. Natl. Acad. Sci. USA 99, 8695–8700 (2002).

    Article  CAS  Google Scholar 

  46. Bernstein, B.E., Tong, J.K. & Schreiber, S.L. Genomewide studies of histone deacetylase function in yeast. Proc. Natl. Acad. Sci. USA 97, 13708–13713 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Tanay for guidance and ideas and all the members of the Kupiec and Shamir laboratories for discussions and encouragement. This work was supported in part by grants from the Israel Science Foundation to M.K. and R.S. and a grant from the Israeli Ministry of Science and Technology to M.K.

Author information

Authors and Affiliations

  1. Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, 69978, Israel

    Israel Steinfeld & Martin Kupiec

  2. School of Computer Science, Tel Aviv University, Ramat Aviv, 69978, Israel

    Israel Steinfeld & Ron Shamir

Authors
  1. Israel Steinfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ron Shamir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Kupiec
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Kupiec.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Complete hierarchical clustering solution for all K-S scores. (PDF 178 kb)

Supplementary Fig. 2

Yap6_(ypd) and Skn7_(h2o2lo) activated genes. (PDF 76 kb)

Supplementary Table 1

The publications from which the gene expression data were obtained. (PDF 37 kb)

Supplementary Table 2

All KS scores. (PDF 1844 kb)

Supplementary Table 3

Unique pairs of TFs and CMs. (XLS 39 kb)

Supplementary Table 4

TATA-containing cohorts. (PDF 19 kb)

Supplementary Note (PDF 78 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Steinfeld, I., Shamir, R. & Kupiec, M. A genome-wide analysis in Saccharomyces cerevisiae demonstrates the influence of chromatin modifiers on transcription. Nat Genet 39, 303–309 (2007). https://doi.org/10.1038/ng1965

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1965

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