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Circadian coupling orchestrates cell growth

Nature Physics volume 21, pages 768–777 (2025)Cite this article

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Abstract

Single-cell circadian oscillators exchange extracellular information to sustain coherent circadian rhythms at the tissue level. The circadian clock and the cell cycle couple within cells but the mechanisms underlying this interplay are poorly understood. We show that the loss of extracellular circadian synchronization disrupts circadian and cell cycle coordination within individual cells, impeding collective tissue growth. We use the theory of coupled oscillators combined with live population, and single-cell recordings and precise experimental perturbations. Coherent circadian rhythms yield oscillatory growth patterns, which unveil a global timing regulator of tissue dynamics. Knocking out core circadian elements abolishes the observed effects, highlighting the central role of circadian clock regulation. Our results underscore the role of tissue-level circadian disruption in regulating proliferation, thereby linking disrupted circadian clocks with oncogenic processes. These findings illuminate the intricate interplay between circadian rhythms, cellular signalling and tissue physiology and enhance our understanding of tissue homeostasis and growth regulation in the context of both health and disease.

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Fig. 1: Framework for identifying extracellular and intracellular circadian and cell cycle interactions.
Fig. 2: Extracellular circadian coupling modulates the intracellular relation with the cell cycle.
Fig. 3: Extracellular circadian coupling controls the growth rate.
Fig. 4: Synchronization of circadian clock modulates the length of the cell cycle.

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Data availability

All the data generated and used for this investigation are available via Figshare at https://doi.org/10.6084/m9.figshare.28375358.v1 (ref. 66).

Code availability

The code used in this study can be found at https://github.com/Granada-Lab/Circadian-clock-cell-cycle and https://github.com/Granada-Lab/Automatic-single-cell-tracking-of-fading-objects. We used Python v.3.8.8. and the following packages: Seaborn (v.0.11.2), Matplotlib (v.3.6.3), NumPy (v.1.23.3), pandas (v.1.4.4), SciPy (v.1.9.1), Skimage (v.0.20.0) and pyBOAT (v.0.9.1).

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Acknowledgements

We would like to extend our gratitude to H.-Y. Liou for his invaluable assistance in the establishment of the automatic tracking pipeline with ilastik. We thank the AMBIO imaging facility of the Charité Berlin for support in the acquisition of real-time fluorescence data. This work was financially supported by the German Federal Ministry for Education and Research through the e:Med Juniorverbund DeepLTNBC TP 3 - 01ZX1917C programme. M.S.N. and M.H.J. acknowledge support from the Independent Research Fund Denmark (Grant No. 9040-00116B) and the Novo Nordisk Foundation (Grant No. NNF20OC0064978). M.S.H. acknowledges support from the Lundbeck Foundation. C.E. is thankful for the support of the Berlin School of Integrative Oncology.

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Authors and Affiliations

  1. Charité Universitätsmedizin Berlin, Berlin, Germany

    Nica Gutu, Marlena Kuhn, Carolin Ector, Marie Möser, Anna-Marie Finger, Ulrich Keilholz, Achim Kramer & Adrián E. Granada

  2. Humboldt Universität zu Berlin, Berlin, Germany

    Nica Gutu, Carolin Ector & Hanspeter Herzel

  3. Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark

    Malthe S. Nordentoft, Mathias Spliid Heltberg & Mogens Høgh Jensen

  4. German Cancer Consortium (DKTK), Berlin, Germany

    Ulrich Keilholz & Adrián E. Granada

  5. Institute for Theoretical Biology, Berlin, Germany

    Hanspeter Herzel

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  1. Nica Gutu
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Contributions

N.G. and A.E.G. were responsible for conceptualization and investigation. N.G., M.S.N. and A.E.G. were responsible for developing the methodology. The experiments were run by N.G., M.K., C.E., M.M. and A.F. The results were visualized by N.G. and A.E.G. A.E.G., M.H.J. and M.S.H. acquired funding. The project was administered and supervised by A.E.G. N.G. and M.S.N. wrote the original draft of the manuscript. N.G., M.S.N., C.E. and A.E.G. reviewed and edited the manuscript. Intellectual support was provided by U.K., A.K., M.H.J., M.S.H. and H.H.

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Correspondence to Adrián E. Granada.

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Gutu, N., Nordentoft, M.S., Kuhn, M. et al. Circadian coupling orchestrates cell growth. Nat. Phys. 21, 768–777 (2025). https://doi.org/10.1038/s41567-025-02838-4

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