Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells.

Jonathan Bieler,David Gatfield,Cedric Gobet,Felix Naef,Kyle Gustafson,Rosamaria Cannavo

doi:10.15252/msb.20145218

Jonathan Bieler, David Gatfield + Show 4 more

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https://doi.org/10.15252/msb.20145218

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Abstract

Circadian cycles and cell cycles are two fundamental periodic processes with a period in the range of 1 day. Consequently, coupling between such cycles can lead to synchronization. Here, we estimated the mutual interactions between the two oscillators by time-lapse imaging of single mammalian NIH3T3 fibroblasts during several days. The analysis of thousands of circadian cycles in dividing cells clearly indicated that both oscillators tick in a 1:1 mode-locked state, with cell divisions occurring tightly 5 h before the peak in circadian Rev-Erbα-YFP reporter expression. In principle, such synchrony may be caused by either unidirectional or bidirectional coupling. While gating of cell division by the circadian cycle has been most studied, our data combined with stochastic modeling unambiguously show that the reverse coupling is predominant in NIH3T3 cells. Moreover, temperature, genetic, and pharmacological perturbations showed that the two interacting cellular oscillators adopt a synchronized state that is highly robust over a wide range of parameters. These findings have implications for circadian function in proliferative tissues, including epidermis, immune cells, and cancer.

Highlights

Understanding how cellular processes interact on multiple levels is of fundamental importance in systems biology
Since the cell cycle duration in many mammalian cells lines is in the range of the period of the circadian oscillator, this leads to the possibility that the two cycles could synchronize
Circadian and cell cycle oscillators in individual cells and tissues provide a system in which two fundamental periodic processes may reciprocally influence each other

Summary

Introduction

Understanding how cellular processes interact on multiple levels is of fundamental importance in systems biology. In this context, the interconnection between circadian and cell cycle oscillators presents an ideal system that can be analyzed in single prokaryotic (Yang et al, 2010) and eukaryotic cells (Nagoshi et al, 2004; Welsh et al, 2004). The circadian clock is a cellautonomous and self-sustained oscillator with a period of about 24 h and thought to function as a cellular metronome that temporally controls key aspects of cell physiology, including metabolism, redox balance, chromatin landscapes and transcriptional states, and cell signaling (Dibner et al, 2010; O’Neill et al, 2013). The system may switch from asynchrony (quasi-periodicity) to synchronization characterized by a rational winding number (p:q) such that exactly p cycles of the first oscillator are completed while the second completes q cycles (Glass, 2001)

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