Model-based Investigation of the Circadian Clock and Cell Cycle Coupling in Mouse Embryonic Fibroblasts: Prediction of RevErb-α Up-regulation During Mitosis

International audienceExperimental 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. Some mathematical models have also been built to assess conditions of control of the cell cycle by the circadian clock, with applications to cancer chronotherapy optimization. However, recent studies in individual NIH3T3 fibroblasts have shown an unexpected acceleration of the circadian clock together with the cell cycle when the culture medium is enriched with growth factors, and the absence of such acceleration in confluent cells. In order to explain these observations , we have studied a possible entrainment of the circadian clock by the cell cycle through a regulation of clock genes around the mitosis phase. We developed a computational model in Biocham with a formal specification of the observed behavior in quantitative temporal logic to investigate the conditions of entrainment in period and phase. We showed that either the selective activation of RevErb-α or the selective inhibition of Bmal1 transcription during the mitosis phase, allowed us to fit the experimental data on both period and phase, while a uniform inhibition of transcription during mitosis seems incompatible with the phase data. We conclude on the arguments favoring the RevErb-α up-regulation hypothesis and on some further predictions of the model