Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 27, Pages 9828-9833Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1320474111
Keywords
coupled oscillators; oscillations; circadian rhythms; gating
Categories
Funding
- ERASysBio+ project C5Sys through Biotechnology and Biological Sciences Research Council (BBSRC) [BB/I004521/1]
- ZonMW Grant [90.201.127]
- Agence Nationale de la Recherche (ANR) [ANR-2009-SYSB-002-02]
- Engineering and Physical Sciences Research Council [GR/S29256/01]
- BBSRC [BB/F005814/1, BB/K003097/1]
- Netherlands Genomic Initiative/Netherlands Organization for Scientific Research [050-060-510]
- ANR [ANR-11-LABEX-0028-01]
- BBSRC [BB/I004521/1, BB/K003097/1, BB/F005814/1] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [24790309] Funding Source: KAKEN
- Biotechnology and Biological Sciences Research Council [BB/F005814/1, BB/I004521/1, BB/K003097/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [GR/S29256/01] Funding Source: researchfish
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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.
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