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

Abstract

A significant fraction of the Saccharomyces 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.

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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.

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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 number GSE8799.

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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

Correspondence to Steven 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)

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Orlando, D., Lin, C., Bernard, A. et al. Global control of cell-cycle transcription by coupled CDK and network oscillators. Nature 453, 944–947 (2008) doi:10.1038/nature06955

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