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Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9828-33. doi: 10.1073/pnas.1320474111. Epub 2014 Jun 23.

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.

Author information

1
Université Nice Sophia Antipolis, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut de Biologie Valrose, 06108 Nice, France;
2
Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom;
3
Department of Genetics, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands; and.
4
Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom;Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S776 "Rythmes biologiques et cancers," Paul Brousse Hospital, 94804 Villejuif, France.
5
Department of Genetics, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands; and g.vanderhorst@erasmusmc.nl delaunay@unice.fr d.a.rand@warwick.ac.uk.
6
Université Nice Sophia Antipolis, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut de Biologie Valrose, 06108 Nice, France; g.vanderhorst@erasmusmc.nl delaunay@unice.fr d.a.rand@warwick.ac.uk.
7
Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom; g.vanderhorst@erasmusmc.nl delaunay@unice.fr d.a.rand@warwick.ac.uk.

Abstract

Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level. Here we use multispectral imaging of single live cells, computational methods, and mathematical modeling to address this question in proliferating mouse fibroblasts. We show that in unsynchronized cells the cell cycle and circadian clock robustly phase lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators oscillate in a synchronized way with a common frequency. Dexamethasone-induced synchronization reveals additional clock states. As well as the low-period phase-locked state there are distinct coexisting states with a significantly higher period clock. Cells transition to these states after dexamethasone synchronization. The temporal coordination of cell division by phase locking to the clock at a single-cell level has significant implications because disordered circadian function is increasingly being linked to the pathogenesis of many diseases, including cancer.

KEYWORDS:

circadian rhythms; coupled oscillators; gating; oscillations

PMID:
24958884
PMCID:
PMC4103330
DOI:
10.1073/pnas.1320474111
[Indexed for MEDLINE]
Free PMC Article

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