Modeling circadian clock–cell cycle interaction effects on cell population growth rates

• Published in: Journal of theoretical biology Vol. 363; pp. 318 - 331
• Main Authors: El Cheikh, R., Bernard, S., El Khatib, N.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 21-12-2014; Elsevier
• Subjects: Age-structured equations; ARNTL Transcription Factors - genetics; Cell Cycle - physiology; Cell Cycle Proteins - metabolism; Cell Proliferation - physiology; Chronotherapy; Chronotherapy - methods; Circadian Clocks - genetics; Circadian Clocks - physiology; Cryptochromes - genetics; Dynamical Systems; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Humans; Mathematics; Models, Theoretical; Mutation - genetics; Nuclear Proteins - metabolism; Period Circadian Proteins - genetics; Protein-Tyrosine Kinases - metabolism; Time Factors; Chronotherapy; Age-structured equations; age-structured equations; chronotherapy; cell cycle; circadian clock
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2014.08.008

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 24h and above 48h. 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 Cry 1, Cry 2 mutations decrease the growth rate of cells, Per 2 mutation enhances it and Bmal 1 knockout increases it for autonomous periods of the cell cycle less than 21h 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.
•We develop a mathematical model for cell cycle–circadian clock coupling.•We characterize multiple regions of cell cycle entrainment by the circadian clock.•Influence of coupling on cell proliferation is studied.•Coupling increases growth rate for cell cycle period around 24h and >48h.•Effects of mutating clock genes on the growth rate are studied.