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Structure and function of a transcriptional network activated by the MAPK Hog1

Nature Genetics volume 40, pages 1300–1306 (2008)Cite this article

Abstract

Cells regulate gene expression using a complex network of signaling pathways, transcription factors and promoters. To gain insight into the structure and function of these networks, we analyzed gene expression in single- and multiple-mutant strains to build a quantitative model of the Hog1 MAPK-dependent osmotic stress response in budding yeast. Our model reveals that the Hog1 and general stress (Msn2/4) pathways interact, at both the signaling and promoter level, to integrate information and create a context-dependent response. This study lays out a path to identifying and characterizing the role of signal integration and processing in other gene regulatory networks.

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Figure 1: Single- and double-mutant analysis of gene expression.
Figure 2: Role of Hog1 and Msn2/4 in osmotic stress–dependent gene induction.
Figure 3: Mechanism of Hog1-dependent gene activation.
Figure 4: ChIP analysis of Sko1 and Hot1 binding sites.
Figure 5: Structure of the transcriptional network activated by the MAPK Hog1.
Figure 6: Context-dependent gene activation by the Hog1–Msn2/4 network.

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References

  1. Alon, U. An Introduction to Systems Biology: Design Principles of Biological Circuits (Chapman & Hall/CRC, Boca Raton, Florida, 2007).

    Google Scholar 

  2. Davidson, E.H. The Regulatory Genome: Gene Regulatory Networks in Development and Evolution (Academic, Burlington, Massachusetts, 2006).

    Google Scholar 

  3. Boyer, L.A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Hu, Z., Killion, P.J. & Iyer, V.R. Genetic reconstruction of a functional transcriptional regulatory network. Nat. Genet. 39, 683–687 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Avery, L. & Wasserman, S. Ordering gene function: the interpretation of epistasis in regulatory hierarchies. Trends Genet. 8, 312–316 (1992).

    Article  CAS  Google Scholar 

  8. Lee, T.I. et al. Redundant roles for the TFIID and SAGA complexes in global transcription. Nature 405, 701–704 (2000).

    Article  CAS  Google Scholar 

  9. Van Driessche, N. et al. Epistasis analysis with global transcriptional phenotypes. Nat. Genet. 37, 471–477 (2005).

    Article  CAS  Google Scholar 

  10. O'Rourke, S.M. & Herskowitz, I. Unique and redundant roles for HOG MAPK pathway components as revealed by whole-genome expression analysis. Mol. Biol. Cell 15, 532–542 (2004).

    Article  CAS  Google Scholar 

  11. Roberts, C.J. et al. Signaling and circuitry of multiple MAPK pathways revealed by a matrix of global gene expression profiles. Science 287, 873–880 (2000).

    Article  CAS  Google Scholar 

  12. Eichenberger, P. et al. The program of gene transcription for a single differentiating cell type during sporulation in Bacillus subtilis. PLoS Biol. 2, e328 (2004).

    Article  Google Scholar 

  13. Horovitz, A. & Fersht, A.R. Co-operative interactions during protein folding. J. Mol. Biol. 224, 733–740 (1992).

    Article  CAS  Google Scholar 

  14. Reiser, V., Ruis, H. & Ammerer, G. Kinase activity-dependent nuclear export opposes stress-induced nuclear accumulation and retention of Hog1 mitogen-activated protein kinase in the budding yeast Saccharomyces cerevisiae. Mol. Biol. Cell 10, 1147–1161 (1999).

    Article  CAS  Google Scholar 

  15. Rep, M., Krantz, M., Thevelein, J.M. & Hohmann, S. The transcriptional response of Saccharomyces cerevisiae to osmotic shock. Hot1p and Msn2p/Msn4p are required for the induction of subsets of high osmolarity glycerol pathway-dependent genes. J. Biol. Chem. 275, 8290–8300 (2000).

    Article  CAS  Google Scholar 

  16. Garreau, H. et al. Hyperphosphorylation of Msn2p and Msn4p in response to heat shock and the diauxic shift is inhibited by cAMP in Saccharomyces cerevisiae. Microbiology 146, 2113–2120 (2000).

    Article  CAS  Google Scholar 

  17. De Wever, V., Reiter, W., Ballarini, A., Ammerer, G. & Brocard, C. A dual role for PP1 in shaping the Msn2-dependent transcriptional response to glucose starvation. EMBO J. 24, 4115–4123 (2005).

    Article  CAS  Google Scholar 

  18. Beck, T. & Hall, M.N. The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402, 689–692 (1999).

    Article  CAS  Google Scholar 

  19. de Nadal, E., Casadome, L. & Posas, F. Targeting the MEF2-like transcription factor Smp1 by the stress-activated Hog1 mitogen-activated protein kinase. Mol. Cell. Biol. 23, 229–237 (2003).

    Article  CAS  Google Scholar 

  20. Nevitt, T., Pereira, J., Azevedo, D., Guerreiro, P. & Rodrigues-Pousada, C. Expression of YAP4 in Saccharomyces cerevisiae under osmotic stress. Biochem. J. 379, 367–374 (2004).

    Article  CAS  Google Scholar 

  21. Proft, M. & Serrano, R. Repressors and upstream repressing sequences of the stress-regulated ENA1 gene in Saccharomyces cerevisiae: bZIP protein Sko1p confers HOG-dependent osmotic regulation. Mol. Cell. Biol. 19, 537–546 (1999).

    Article  CAS  Google Scholar 

  22. Rep, M. et al. Osmotic stress-induced gene expression in Saccharomyces cerevisiae requires Msn1p and the novel nuclear factor Hot1p. Mol. Cell. Biol. 19, 5474–5485 (1999).

    Article  CAS  Google Scholar 

  23. Rep, M. et al. The Saccharomyces cerevisiae Sko1p transcription factor mediates HOG pathway-dependent osmotic regulation of a set of genes encoding enzymes implicated in protection from oxidative damage. Mol. Microbiol. 40, 1067–1083 (2001).

    Article  CAS  Google Scholar 

  24. Proft, M., Gibbons, F.D., Copeland, M., Roth, F.P. & Struhl, K. Genomewide identification of Sko1 target promoters reveals a regulatory network that operates in response to osmotic stress in Saccharomyces cerevisiae. Eukaryot. Cell 4, 1343–1352 (2005).

    Article  CAS  Google Scholar 

  25. Gorner, W. et al. Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity. Genes Dev. 12, 586–597 (1998).

    Article  CAS  Google Scholar 

  26. Erasmus, D.J. & van der Merwe, G.K. & van Vuuren, H.J. Genome-wide expression analyses: metabolic adaptation of Saccharomyces cerevisiae to high sugar stress. FEMS Yeast Res 3, 375–399 (2003).

    Article  CAS  Google Scholar 

  27. Reiser, V., Raitt, D.C. & Saito, H. Yeast osmosensor Sln1 and plant cytokinin receptor Cre1 respond to changes in turgor pressure. J. Cell Biol. 161, 1035–1040 (2003).

    Article  CAS  Google Scholar 

  28. Hohmann, S., Krantz, M. & Nordlander, B. Yeast osmoregulation. Methods Enzymol. 428, 29–45 (2007).

    Article  CAS  Google Scholar 

  29. Gasch, A.P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).

    Article  CAS  Google Scholar 

  30. Mettetal, J.T., Muzzey, D., Gomez-Uribe, C. & van Oudenaarden, A. The frequency dependence of osmo-adaptation in Saccharomyces cerevisiae. Science 319, 482–484 (2008).

    Article  CAS  Google Scholar 

  31. Proft, M. & Struhl, K. MAP kinase-mediated stress relief that precedes and regulates the timing of transcriptional induction. Cell 118, 351–361 (2004).

    Article  CAS  Google Scholar 

  32. Durchschlag, E., Reiter, W., Ammerer, G. & Schuller, C. Nuclear localization destabilizes the stress-regulated transcription factor Msn2. J. Biol. Chem. 279, 55425–55432 (2004).

    Article  CAS  Google Scholar 

  33. Robyr, D., Kurdistani, S.K. & Grunstein, M. Analysis of genome-wide histone acetylation state and enzyme binding using DNA microarrays. Methods Enzymol. 376, 289–304 (2004).

    Article  CAS  Google Scholar 

  34. Bohlander, S.K., Espinosa, R. III, Le Beau, M.M., Rowley, J.D. & Diaz, M.O. A method for the rapid sequence-independent amplification of microdissected chromosomal material. Genomics 13, 1322–1324 (1992).

    Article  CAS  Google Scholar 

  35. Iyer, V.R. et al. Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature 409, 533–538 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Steger, D. Wykoff, A. Carroll and C. Hopkins from Agilent for advice regarding microarray, ChIP and other procedures; T. Lee and R. Young for sharing their tiling-array design and hybridization protocol before publication; H. Margalit and members of the O'Shea, Friedman and Regev laboratories for helpful discussions; and P. Grosu for help with Rosetta Resolver. We are also grateful to E. Lander, D. Pe'er, D. Koller, R. Losick, M. Brenner and B. Stern for reading the manuscript before publication. A.P.C. was a Howard Hughes Medical Institute (HHMI) Fellow of the Life Sciences Research Foundation and A.R. was supported by a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. This work was supported by HHMI (E.K.O.) and a grant from the Human Frontiers Science Program (E.K.O., A.R. and N.F.).

Author information

Authors and Affiliations

  1. Departments of Molecular and Cellular Biology and Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University Faculty of Arts and Sciences Center for Systems Biology, Northwest Labs, 52 Oxford Street, Cambridge, 02138, Massachusetts, USA

    Andrew P Capaldi, Ying Liu & Erin K O'Shea

  2. School of Computer Science and Engineering, The Hebrew University, Jerusalem, 91904, Israel

    Tommy Kaplan, Naomi Habib & Nir Friedman

  3. Department of Molecular Genetics and Biotechnology, Faculty of Medicine, The Hebrew University, Jerusalem, 91120, Israel

    Tommy Kaplan & Naomi Habib

  4. Department of Biology, Massachusetts Institute of Technology and The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Aviv Regev

Authors
  1. Andrew P Capaldi
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Correspondence to Erin K O'Shea.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Note and Supplementary Methods (PDF 1905 kb)

Supplementary table 1

Raw data for KCl stress and YEPD experiments (XLS 9579 kb)

Supplementary table 2

Expression component data for KCl experiments (gene in Hog1 network) (XLS 200 kb)

Supplementary table 3

Expression component data for KCl experiments (all genes) (XLS 16376 kb)

Supplementary table 4

Raw data for glucose experiments (XLS 1889 kb)

Supplementary table 5

Expression component data for glucose experiments (all genes) (XLS 2122 kb)

Supplementary table 6

List of strains used in this study (XLS 39 kb)

Supplementary table 7

Microscopy images and data (XLS 5256 kb)

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Capaldi, A., Kaplan, T., Liu, Y. et al. Structure and function of a transcriptional network activated by the MAPK Hog1. Nat Genet 40, 1300–1306 (2008). https://doi.org/10.1038/ng.235

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