Movatterモバイル変換

[0]ホーム
URL:

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.

Advertisement

Nature
  • Letter
  • Published:

Global control of cell-cycle transcription by coupled CDK and network oscillators

Naturevolume 453, pages944–947 (2008)Cite this article

Abstract

A significant fraction of theSaccharomyces cerevisiae genome is transcribed periodically during the cell division cycle1,2, indicating that properly timed gene expression is important for regulating cell-cycle events. Genomic analyses of the localization and expression dynamics of transcription factors suggest that a network of sequentially expressed transcription factors could control the temporal programme of transcription during the cell cycle3. However, directed studies interrogating small numbers of genes indicate that their periodic transcription is governed by the activity of cyclin-dependent kinases (CDKs)4. To determine the extent to which the global cell-cycle transcription programme is controlled by cyclin–CDK complexes, we examined genome-wide transcription dynamics in budding yeast mutant cells that do not express S-phase and mitotic cyclins. Here we show that a significant fraction of periodic genes are aberrantly expressed in the cyclin mutant. Although cells lacking cyclins are blocked at the G1/S border, nearly 70% of periodic genes continued to be expressed periodically and on schedule. Our findings reveal that although CDKs have a function in the regulation of cell-cycle transcription, they are not solely responsible for establishing the global periodic transcription programme. We propose that periodic transcription is an emergent property of a transcription factor network that can function as a cell-cycle oscillator independently of, and in tandem with, the CDK oscillator.

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

Access options

Access through your institution

Subscription info for Japanese customers

We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

￥ 4,980

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

Figure 1:Dynamics of periodic transcripts in wild-type and cyclin-mutant cells.
Figure 2:Transcription dynamics of established cyclin–CDK-regulated genes.
Figure 3:Genes showing altered behaviours in cyclin-mutant cells.
Figure 4:The periodic transcription programme is largely intact in cyclin-mutant cells that arrest at the G1/S border.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus (GEO,http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO series accession numberGSE8799.

References

  1. Pramila, T., Wu, W., Miles, S., Noble, W. S. & Breeden, L. L. The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle.Genes Dev.20, 2266–2278 (2006)

    Article CAS  Google Scholar 

  2. Spellman, P. T. et al. Comprehensive identification of cell cycle-regulated genes of the yeastSaccharomyces cerevisiae by microarray hybridization.Mol. Biol. Cell9, 3273–3297 (1998)

    Article CAS  Google Scholar 

  3. Simon, I. et al. Serial regulation of transcriptional regulators in the yeast cell cycle.Cell106, 697–708 (2001)

    Article CAS  Google Scholar 

  4. Wittenberg, C. & Reed, S. I. Cell cycle-dependent transcription in yeast: Promoters, transcription factors, and transcriptomes.Oncogene24, 2746–2755 (2005)

    Article CAS  Google Scholar 

  5. Murray, A. W. Recycling the cell cycle: Cyclins revisited.Cell116, 221–234 (2004)

    Article CAS  Google Scholar 

  6. Zwicker, J. & Muller, R. Cell cycle-regulated transcription in mammalian cells.Prog. Cell Cycle Res.1, 91–99 (1995)

    Article CAS  Google Scholar 

  7. Cho, R. J. et al. A genome-wide transcriptional analysis of the mitotic cell cycle.Mol. Cell2, 65–73 (1998)

    Article CAS  Google Scholar 

  8. Ren, B. et al. Genome-wide location and function of DNA binding proteins.Science290, 2306–2309 (2000)

    Article ADS CAS  Google Scholar 

  9. Lee, T. I. et al. Transcriptional regulatory networks inSaccharomyces cerevisiae .Science298, 799–804 (2002)

    Article ADS CAS  Google Scholar 

  10. Haase, S. B. & Reed, S. I. Evidence that a free-running oscillator drives G1 events in the budding yeast cell cycle.Nature401, 394–397 (1999)

    ADS CAS  Google Scholar 

  11. Haase, S. B., Winey, M. & Reed, S. I. Multi-step control of spindle pole body duplication by cyclin-dependent kinase.Nature Cell Biol.3, 38–42 (2001)

    Article CAS  Google Scholar 

  12. Lew, D. J. & Reed, S. I. Morphogenesis in the yeast cell cycle: Regulation by Cdc28 and cyclins.J. Cell Biol.120, 1305–1320 (1993)

    Article CAS  Google Scholar 

  13. de Lichtenberg, U. et al. Comparison of computational methods for the identification of cell cycle-regulated genes.Bioinformatics21, 1164–1171 (2005)

    Article CAS  Google Scholar 

  14. Amon, A., Tyers, M., Futcher, B. & Nasmyth, K. Mechanisms that help the yeast cell cycle clock tick: G2 cyclins transcriptionally activate G2 cyclins and repress G1 cyclins.Cell74, 993–1007 (1993)

    Article CAS  Google Scholar 

  15. Koch, C., Schleiffer, A., Ammerer, G. & Nasmyth, K. Switching transcription on and off during the yeast cell cycle: Cln/Cdc28 kinases activate bound transcription factor SBF (Swi4/Swi6) at start, whereas Clb/Cdc28 kinases displace it from the promoter in G2.Genes Dev.10, 129–141 (1996)

    Article CAS  Google Scholar 

  16. Toyn, J. H., Johnson, A. L., Donovan, J. D., Toone, W. M. & Johnston, L. H. The Swi5 transcription factor ofSaccharomyces cerevisiae has a role in exit from mitosis through induction of the CDK-inhibitor Sic1 in telophase.Genetics145, 85–96 (1997)

    CAS  Google Scholar 

  17. Knapp, D., Bhoite, L., Stillman, D. J. & Nasmyth, K. The transcription factor Swi5 regulates expression of the cyclin kinase inhibitor p40SIC1.Mol. Cell. Biol.16, 5701–5707 (1996)

    Article CAS  Google Scholar 

  18. Moll, T., Tebb, G., Surana, U., Robitsch, H. & Nasmyth, K. The role of phosphorylation and the CDC28 protein kinase in cell cycle-regulated nuclear import of theS. cerevisiae transcription factor, SWI5.Cell66, 743–758 (1991)

    Article CAS  Google Scholar 

  19. O’Conallain, C., Doolin, M. T., Taggart, C., Thornton, F. & Butler, G. Regulated nuclear localisation of the yeast transcription factor Ace2p controls expression of chitinase (CTS1) inSaccharomyces cerevisiae .Mol. Gen. Genet.262, 275–282 (1999)

    Article  Google Scholar 

  20. Zhu, G. et al. Two yeast forkhead genes regulate the cell cycle and pseudohyphal growth.Nature406, 90–94 (2000)

    Article ADS CAS  Google Scholar 

  21. Kumar, R. et al. Forkhead transcription factors, Fkh1p and Fkh2p, collaborate with Mcm1p to control transcription required for M-phase.Curr. Biol.10, 896–906 (2000)

    Article CAS  Google Scholar 

  22. Frey, B. J. & Dueck, D. Clustering by passing messages between data points.Science315, 972–976 (2007)

    Article ADS MathSciNet CAS  Google Scholar 

  23. Harbison, C. T. et al. Transcriptional regulatory code of a eukaryotic genome.Nature431, 99–104 (2004)

    Article ADS CAS  Google Scholar 

  24. Costanzo, M. et al. CDK activity antagonizes Whi5, an inhibitor of G1/S transcription in yeast.Cell117, 899–913 (2004)

    Article CAS  Google Scholar 

  25. de Bruin, R. A. et al. Constraining G1-specific transcription to late G1 phase: the MBF-associated corepressor Nrm1 acts via negative feedback.Mol. Cell23, 483–496 (2006)

    Article CAS  Google Scholar 

  26. Ho, Y., Costanzo, M., Moore, L., Kobayashi, R. & Andrews, B. J. Regulation of transcription at theSaccharomyces cerevisiae start transition by Stb1, a Swi6-binding protein.Mol. Cell. Biol.19, 5267–5278 (1999)

    Article CAS  Google Scholar 

  27. Pic-Taylor, A., Darieva, Z., Morgan, B. A. & Sharrocks, A. D. Regulation of cell cycle-specific gene expression through cyclin-dependent kinase-mediated phosphorylation of the forkhead transcription factor Fkh2p.Mol. Cell. Biol.24, 10036–10046 (2004)

    Article CAS  Google Scholar 

  28. Sidorova, J. M., Mikesell, G. E. & Breeden, L. L. Cell cycle-regulated phosphorylation of Swi6 controls its nuclear localization.Mol. Biol. Cell6, 1641–1658 (1995)

    Article CAS  Google Scholar 

  29. Ubersax, J. A. et al. Targets of the cyclin-dependent kinase Cdk1.Nature425, 859–864 (2003)

    Article ADS CAS  Google Scholar 

  30. Teixeira, M. C. et al. The YEASTRACT database: A tool for the analysis of transcription regulatory associations inSaccharomyces cerevisiae .Nucleic Acids Res.34, D446–D451 (2006)

    Article CAS  Google Scholar 

  31. Li, C. & Wong, W. H. Model-based analysis of oligonucleotide arrays: model validation, design issues and standard error application.Genome Biol.2 research0032.1–0032.11 doi: 10.1186/gb-2001-2-8-research0032 (2001)

    Article  Google Scholar 

  32. Orlando, D. A. et al. A probabilistic model for cell cycle distributions in synchrony experiments.Cell Cycle6, 478–488 (2007)

    Article CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Lew and L. Simmons Kovacs for discussions and critical reading of the manuscript, and P. Benfey for helpful discussions and support. Financial support was provided by the American Cancer Society (to S.B.H.), the Alfred P. Sloan Foundation (to A.J.H.), the National Science Foundation (to A.J.H. and J.E.S.S.) and the National Institutes of Health (to S.B.H., A.J.H. and J.E.S.S.).

Author Contributions D.A.O., C.Y.L. and S.B.H. designed and performed the experiments. J.Y.W. provided technical expertise. D.A.O., C.Y.L., A.B., E.S.I. and A.J.H. performed the computational analyses, with contributions from J.E.S.S. and S.B.H. to the boolean model. D.A.O. and S.B.H. prepared the manuscript with contributions from C.Y.L., A.B., E.S.I. and A.J.H.

Author information

Authors and Affiliations

  1. Department of Biology,,

    David A. Orlando, Charles Y. Lin, Jean Y. Wang & Steven B. Haase

  2. Program in Computational Biology and Bioinformatics,,

    David A. Orlando

  3. Department of Computer Science,,

    Allister Bernard & Alexander J. Hartemink

  4. Department of Physics, and,

    Joshua E. S. Socolar

  5. Department of Statistical Science, Duke University, Durham, North Carolina 27708, USA,

    Edwin S. Iversen

Authors
  1. David A. Orlando
  2. Charles Y. Lin
  3. Allister Bernard
  4. Jean Y. Wang
  5. Joshua E. S. Socolar
  6. Edwin S. Iversen
  7. Alexander J. Hartemink
  8. Steven B. Haase

Corresponding author

Correspondence toSteven B. Haase.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-4, 6-15, 17, and 19 with Legends. It also contains Supplementary Methods with more complete details on the methods/analyses presented in the main manuscript. Supplementary Tables 3-9 with Legends, as well as Legends for Supplementary Tables 1 and 2 are included. (PDF 3721 kb)

Supplementary Figure 5

The file contains Supplementary Figure 5 with Legend. Each page (30 pages) displays the transcript profile of every gene from a wild-type cluster and its component cyclin mutant sub-clusters from Figure 3 as line-graphs with cluster centroids and within cluster Pearson correlations provided. (PDF 279 kb)

Supplementary Figure 16

The file contains Supplementary Figure 16 with Legend. Each page (11 pages) displays the transcript profile of every gene from a wild-type cluster and its component cyclin mutant sub-clusters from Supplementary Figure 15 as line-graphs with cluster centroids and within cluster Pearson correlations provided. (PDF 191 kb)

Supplementary Figure 18

The file contains Supplementary Figure 18 with Legend. Each page (9 pages) displays the transcript profile of every gene from a wild-type cluster and its component cyclin mutant sub-clusters from Supplementary Figure 17 as line-graphs with cluster centroids and within cluster Pearson correlations provided. (PDF 179 kb)

Supplementary Table 1

The file contains Supplementary Table 1. (XLS 302 kb)

Supplementary Table 2

The file contains Supplementary Table 2. (XLS 125 kb)

Rights and permissions

About this article

Cite this article

Orlando, D., Lin, C., Bernard, A.et al. Global control of cell-cycle transcription by coupled CDK and network oscillators.Nature453, 944–947 (2008). https://doi.org/10.1038/nature06955

Download citation

This article is cited by

Access through your institution
Buy or subscribe

Editorial Summary

The cell cycle: More regulators to look for

During the cell cycle, many genes are transcribed in a periodic manner. A new study inSaccharomyces cerevisiae shows that a significant proportion of these genes continue to cycle in the absence of the major cell cycle regulatory cyclin/CDK complexes that control the G1-S transition. This suggests the existence of additional period regulators responsible for the periodic transcription of genes during the cell cycle.

Advertisement

Search

Advanced search

Quick links

Nature Briefing

Sign up for theNature 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
[8]ページ先頭
©2009-2025 Movatter.jp