Molecular noise in gene expression can generate substantial variability in protein concentration1. However, its effect on the precision of a natural eukaryotic circuit such as the control of cell cycle remains unclear. We use single-cell imaging of fluorescently labelled budding yeast to measure times from division to budding (G1) and from budding to the next division. The variability in G1 decreases with the square root of the ploidy through a 1N/2N/4N ploidy series, consistent with simple stochastic models for molecular noise. Also, increasing the gene dosage of G1 cyclins decreases the variability in G1. A new single-cell reporter for cell protein content allows us to determine the contribution to temporal G1 variability of deterministic size control (that is, smaller cells extending G1). Cell size control contributes significantly to G1 variability in daughter cells but not in mother cells. However, even in daughters, size-independent noise is the largest quantitative contributor to G1 variability. Exit of the transcriptional repressor Whi5 from the nucleus partitions G1 into two temporally uncorrelated and functionally distinct steps. The first step, which depends on the G1 cyclin gene CLN3, corresponds to noisy size control that extends G1 in small daughters, but is of negligible duration in mothers. The second step, whose variability decreases with increasing CLN2 gene dosage, is similar in mothers and daughters. This analysis decomposes the regulatory dynamics of the Start transition into two independent modules, a size sensing module and a timing module, each of which is predominantly controlled by a different G1 cyclin.
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We thank J. Haber, E. Bi and the NCRR Yeast Resource Center, University of Washington, for plasmids and strains; P. Nurse and T. Ryan for discussions; and N. Buchler, B. Drapkin, J. Robbins, J. Roberts and J. Widom for comments on the manuscript. This work was supported by the National Institute of Health (J.M.S., E.D.S., F.R.C.), the Howard Hughes Medical Institute (J.M.B.), and the National Science Foundation (E.D.S.).
Author Contributions Experimental work by S.D. and J.M.S.; project planning, data analysis and manuscript preparation by all authors.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
This file contains the Supplementary Materials and Methods, Supplementary Discussion, Supplementary Tables S1- S12 and Supplementary Figures S1-S12. The discussion concerns the statistical analysis of the correlation of αT and ln(Mbirth), the analysis of the independence of the two regulatory steps of Start and a more detailed analysis of movies in glycerol/ethanol. The Supplementary Tables show the cell cycle timing analysis, the analysis of cell size at budding and of growth rates of individual cells. The Supplementary Figures show additional data concerning noise reduction by ploidy and gene dosage, the effect of CLN2 gene on Start and the distribution of growth rates of individual cells. (PDF 916 kb)
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Talia, S., Skotheim, J., Bean, J. et al. The effects of molecular noise and size control on variability in the budding yeast cell cycle. Nature 448, 947–951 (2007). https://doi.org/10.1038/nature06072
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