title: Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells.
abstract: Circadian cycles and cell cycles are two fundamental periodic processes with a period in the range of 1 day. Consequently, coupling between such cycles can lead to synchronization. Here, we estimated the mutual interactions between the two oscillators by time-lapse imaging of single mammalian NIH3T3 fibroblasts during several days. The analysis of thousands of circadian cycles in dividing cells clearly indicated that both oscillators tick in a 1:1 mode-locked state, with cell divisions occurring tightly 5 h before the peak in circadian Rev-Erbα-YFP reporter expression. In principle, such synchrony may be caused by either unidirectional or bidirectional coupling. While gating of cell division by the circadian cycle has been most studied, our data combined with stochastic modeling unambiguously show that the reverse coupling is predominant in NIH3T3 cells. Moreover, temperature, genetic, and pharmacological perturbations showed that the two interacting cellular oscillators adopt a synchronized state that is highly robust over a wide range of parameters. These findings have implications for circadian function in proliferative tissues, including epidermis, immune cells, and cancer.
authors.affiliation: The Institute of Bioengineering, School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bieler
authors.affiliation: The Institute of Bioengineering, School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Cannavo
authors.affiliation: The Institute of Bioengineering, School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Kyle
authors.initials: K
authors.lastname: Gustafson
authors.affiliation: The Institute of Bioengineering, School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Cedric
authors.initials: C
authors.lastname: Gobet
authors.affiliation: Center for Integrative Genomics, Génopode, University of Lausanne, Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Gatfield
authors.affiliation: The Institute of Bioengineering, School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland felix.naef@epfl.ch.
authors.forename: Felix
authors.initials: F
authors.lastname: Naef
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects; D056931:Cryptochromes / Q000378:metabolism; D008322:Mammals / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D013696:Temperature; D059008:Time-Lapse Imaging
chemical_list: C538967:Cry2 protein, mouse; D056931:Cryptochromes; C556792:longdaysin; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D000225:Adenine
keywords: cell cycle; circadian cycle; single cells; synchronization; time‐lapse imaging