Model-Based Investigation of the Effect of the Cell Cycle on the Circadian Clock Through Transcription Inhibition During Mitosis

Experimental observations have put in evidence autonomous self-sustained circadian oscillators in most mammalian cells, and proved the existence of molecular links between the circadian clock and the cell cycle. Several models have been elaborated to assess conditions of control of the cell cycle by the circadian clock, in particular through the regulation by clock genes of Wee1, an inhibitor of the mitosis promoting factor, responsible for a circadian gating of mitosis and cell division period doubling phenomena. However, recent studies in individual NIH3T3 fibroblasts have shown an unexpected acceleration of the circadian clock together with the cell cycle when the milieu is enriched in FBS, the absence of such acceleration in confluent cells, and the absence of any period doubling phenomena. In this paper, we try to explain these observations by a possible entrainment of the circadian clock by the cell cycle through the inhibition of transcription during mitosis. We develop a differential model of that reverse coupling of the cell cycle and the circadian clock and investigate the conditions in which both cycles are mutually entrained. We use the mammalian circadian clock model of Relogio et al. and a simple model of the cell cycle by Qu et al. which focuses on the mitosis phase. We show that our coupled model is able to reproduce the main observations reported by Feillet et al. in individual fibroblast experiments and use it for making some predictions.