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1 DRACULA - Multi-scale modelling of cell dynamics : application to hematopoiesis CGMC - Centre de génétique moléculaire et cellulaire, Inria Grenoble - Rhône-Alpes, ICJ - Institut Camille Jordan Villeurbanne, UCBL - Université Claude Bernard Lyon 1 : EA 2 ICJ - Institut Camille Jordan Villeurbanne 3 UCBL - Université Claude Bernard Lyon 1 4 IXXI - Institut Rhône-Alpin des systèmes complexes 5 Department of Computer Science and Mathematics Beirut

Abstract : The circadian clock and the cell cycle are two tightly coupled oscillators. Recent analytical studies have shown counter-intuitive effects of circadian gating of the cell cycle on growth rates of proliferating cells which cannot be explained by a molecular model or a population model alone. In this work, we present a combined molecular-population model that studies how coupling the circadian clock to the cell cycle, through the protein WEE1, affects a proliferating cell population. We show that the cell cycle can entrain to the circadian clock with different rational period ratios and characterize multiple domains of entrainment. We show that coupling increases the growth rate for autonomous periods of the cell cycle around 24 h and above 48 h. We study the effect of mutation of circadian genes on the growth rate of cells and show that disruption of the circadian clock can lead to abnormal proliferation. Particularly, we show that $\mathit{Cry1}$, $\mathit{Cry2}$ mutations decrease the growth rate of cells, $\mathit{Per2}$ mutation enhances it and $\mathit{Bmal1}$ knockout increases it for autonomous periods of the cell cycle less than 21 h and decreases it elsewhere. Combining a molecular model to a population model offers new insight on the influence of the circadian clock on the growth of a cell population. This can help chronotherapy which takes benefits of physiological rhythms to improve anti-cancer efficacy and tolerance to drugs by administering treatments at a specific time of the day.

Keywords : circadian clock cell cycle chronotherapy age-structured equations

Autor: Raouf El Cheikh - Samuel Bernard - Nader El Khatib -



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