Control of synchronization ratios in clock/cell cycle coupling by growth factors and glucocorticoids.

S Almeida,F Delaunay,M Chaves

doi:10.1098/rsos.192054

Abstract

The cell cycle and the circadian clock are essential cyclic cellular processes often synchronous in healthy cells. In this work, we use previously developed mathematical models of the mammalian cell cycle and circadian cellular clock in order to investigate their dynamical interactions. Firstly, we study unidirectional cell cycle → clock coupling by proposing a mechanism of mitosis promoting factor (MPF)-controlled REV-ERBα degradation. Secondly, we analyse a bidirectional coupling configuration, where we add the CLOCK : BMAL1-mediated MPF repression via the WEE1 kinase to the first system. Our simulations reproduce ratios of clock to cell cycle period in agreement with experimental observations and give predictions of the system’s synchronization state response to a variety of control parameters. Specifically, growth factors accelerate the coupled oscillators and dexamethasone (Dex) drives the system from a 1 : 1 to a 3 : 2 synchronization state. Furthermore, simulations of a Dex pulse reveal that certain time regions of pulse application drive the system from 1 : 1 to 3 : 2 synchronization while others have no effect, revealing the existence of a responsive and an irresponsive system’s phase, a result we contextualize with observations on the segregation of Dex-treated cells into two populations.

Highlights

The cell division cycle and the circadian clock are two fundamental cyclic processes of cellular control that tend to be synchronous in a variety of healthy cell types
Both clock and cell cycle processes are essential for cellular health in mammals and when unregulated can result in disease at the organism level
Feillet et al have verified that for 1 : 1 phase-locking the cell cycle division occurs at a specific clock phase for all cells, while the synchronization dynamics of the second group of 20% FBS after Dex-treatment shows a trimodal frequency peak distribution of mitosis with circadian clock phase

Summary

Introduction

The cell division cycle and the circadian clock are two fundamental cyclic processes of cellular control that tend to be synchronous in a variety of healthy cell types. Feillet et al observed the phase-locking behaviour of cells under the application a of a pulse of dexamethasone (Dex), a synthetic glucocorticoid agonist known to synchronize clocks in populations of mammalian cells [11]. This application resulted in different clock to cell cycle period ratios depending on the concentration of GFs [11]. Feillet et al have verified that for 1 : 1 phase-locking the cell cycle division occurs at a specific clock phase for all cells, while the synchronization dynamics of the second group of 20% FBS after Dex-treatment shows a trimodal frequency peak distribution of mitosis with circadian clock phase. We analyse the effect of a Dex pulse (as opposed to a constant Dex input) in bidirectional coupling and find the time of pulse application Tpulse to be a control parameter for the system’s synchronization response

Methodology

The effect of growth factor

The effect of dexamethasone

Bidirectional coupling

Findings

Adding a dexamethasone pulse: implications for cell populations