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Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle

Nature volume 494, pages 480–483 (2013)Cite this article

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Abstract

Biologists have long been concerned about what constrains variation in cell size, but progress in this field has been slow and stymied by experimental limitations1. Here we describe a new method, ergodic rate analysis (ERA), that uses single-cell measurements of fixed steady-state populations to accurately infer the rates of molecular events, including rates of cell growth. ERA exploits the fact that the number of cells in a particular state is related to the average transit time through that state2. With this method, it is possible to calculate full time trajectories of any feature that can be labelled in fixed cells, for example levels of phosphoproteins or total cellular mass. Using ERA we find evidence for a size-discriminatory process at the G1/S transition that acts to decrease cell-to-cell size variation.

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Figure 1: Dynamic information from static data using ERA.
Figure 2: Calculation of growth as a function of cell cycle progression using ERA.
Figure 3: Rate of cell growth as a function of size and cell cycle.
Figure 4: Effects of drug treatments on size variability at G1 exit.

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Acknowledgements

We thank A. Klein, Y. Merbl, S. Tal and J. Toettcher for consistent and valuable insights at the beginning of and throughout this project. We thank J. Waters and the staff of The Nikon Imaging Center at Harvard Medical School for help and support. We especially thank R. Ward for her critique of the paper and the National Institute of General Medical Sciences (GM26875) for support of this work.

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Author notes

  1. Ran Kafri and Jason Levy: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Ran Kafri, Miriam B. Ginzberg, Seungeun Oh, Galit Lahav & Marc W. Kirschner

  2. Department of Mathematics and Statistics, University of Ottawa, Ottawa, K1N 6N5, Ontario, Canada

    Jason Levy

Authors
  1. Ran Kafri
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  3. Miriam B. Ginzberg
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  4. Seungeun Oh
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  5. Galit Lahav
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  6. Marc W. Kirschner
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Contributions

R.K. and J.L. developed the method (ERA) for extracting dynamic information and calculating feedback spectra from fixed populations, designed algorithms, wrote all image-processing software and analysed data. R.K. designed all experiments and wrote the manuscript. J.L. contributed significantly to all conceptual challenges and to writing the manuscript. M.B.G. contributed conceptually on levels of the study, made many important measurements and calculations and contributed to the writing of the manuscript. S.O. provided interferometry-derived cell mass measurements. G.L. and M.W.K. contributed to the formulation of the problem, development of the ideas and the writing of the manuscript.

Corresponding author

Correspondence to Marc W. Kirschner.

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The authors declare no competing financial interests.

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This file contains Supplementary Text and Data, which includes Supplementary Figures 1-22 and additional references (see Contents for more details). (PDF 5477 kb)

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Kafri, R., Levy, J., Ginzberg, M. et al. Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle. Nature 494, 480–483 (2013). https://doi.org/10.1038/nature11897

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