Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle

Abstract

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 singlecell 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.coupled oscillators | oscillations | circadian rhythms | gating

A comprehensive reduced model of the mammalian cell cycle

“…A two variable cell cycle model based on the negative feedback loop between MPF and the APC:cdc20 complex and on a positive feedback loop of MPF was calibrated from experimental data for cyclin B from one study (Pomerening et al (2005)) and was able to reproduce experimental data from another study (Feillet et al (2014)) for the tunability of the period with the growth factor input.…”

“…7 we can see that the model reproduces the trend of period tunable with a Growth Factor input, where an adjustment is made between our output and experimental data from Table 2. The experimental data points come mostly from Feillet et al (2014), with the exception of the 5% FBS (fetal bovine serum) value, that is an additional measurement done under the exact same experimental conditions (unperturbed NIH 3T3 mouse fibroblasts). We do a scaling in our model such as t → βt, which leads to S GF → S GF β , with β = 0.1.…”

“…The cell cycle of several mammalian cells has a period of approximately 24 h and is coupled to the cellular circadian clock, another important biological oscillator, see Feillet et al (2014) and Feillet et al (2015). Furthermore, the rate of division in a culture of mammalian cells varies accordingly with the amount of "growth factors", which are represented by a specific class of peptidic hormones added to the medium, allowing to tune the period of the oscillator.…”

Circadian Rhythms in Stem Cell Biology and Function

“…light, temperature, hormones, feeding). Therefore, Feillet et al found that synchronizing in vitro cultured cells leads to the occurrence of two subpopulations in culture: one in which the 1:1 phase locking is sustained, and another in which two circadian clock periods coincide with three complete cell cycles (Feillet et al 2014 ). This suggests that the cell cycle is synchronized via physiological stimuli with the circadian clock (Feillet et al 2015 ).…”

“…This mechanism is heavily conserved throughout evolution and allows organisms to adapt and to synchronize themselves to diurnal fl uctuations in their environment. Circadian rhythmicity can be seen in many different life forms, ranging from unicellular organisms, like cyanobacteria, to highly specialized and stem cell heterogeneity (Janich et al 2011 ), cell division (Matsuo et al 2003 ;Kowalska et al 2013 ;Feillet et al 2014 ;Nagoshi et al 2004 ;Yang et al 2009;Unsal-Kaçmaz et al 2005 ), damage induced regeneration (Janich et al 2013 ), immune progenitor cell migration and differentiation (Scheiermann et al 2013 ;Yu et al 2013 ) as reviewed by Steven Brown ( 2014 ).…”