title: Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.
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.
authors: 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;
authors: Céline
authors: C
authors: Feillet
authors: Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom;
authors: Peter
authors: P
authors: Krusche
authors: Department of Genetics, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands; and.
authors: Filippo
authors: F
authors: Tamanini
authors: Department of Genetics, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands; and.
authors: Roel C
authors: RC
authors: Janssens
authors: Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom;
authors: Mike J
authors: MJ
authors: Downey
authors: 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;
authors: Patrick
authors: P
authors: Martin
authors: 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;
authors: Michèle
authors: M
authors: Teboul
authors: Department of Genetics, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands; and.
authors: Shoko
authors: S
authors: Saito
authors: 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.
authors: Francis A
authors: FA
authors: Lévi
authors: Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom;
authors: Till
authors: T
authors: Bretschneider
authors: 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.
authors: Gijsbertus T J
authors: GT
authors: van der Horst
authors: 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.
authors: Franck
authors: F
authors: Delaunay
authors: Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom; g.vanderhorst@erasmusmc.nl delaunay@unice.fr d.a.rand@warwick.ac.uk.
authors: David A
authors: DA
authors: Rand
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002940:Circadian Rhythm / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells
chemical_list: D018797:Cell Cycle Proteins; D003907:Dexamethasone; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: circadian rhythms; coupled oscillators; gating; oscillations