Weak coupling between intracellular feedback loops explains dissociation of clock gene dynamics.

Christoph Schmal,Jihwan Myung,Isao T Tokuda,Ken-Ichi Honma,J Patrick Pett,Hanspeter Herzel,Sato Honma,Daisuke Ono,Didier Gonze

doi:10.1371/journal.pcbi.1007330

Abstract

Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described in recent experimental studies that applied various perturbations such as slice preparations, light pulses, jet-lag, and culture medium exchange. In this paper, we provide evidence that this “presumably transient” dissociation of circadian gene expression oscillations may occur at the single-cell level. Conceptual and detailed mechanistic mathematical modeling suggests that such dissociation is due to a weak interaction between multiple feedback loops present within a single cell. The dissociable loops provide insights into underlying mechanisms and general design principles of the molecular circadian clock.

Highlights

Circadian clocks are omnipresent in almost all living organisms as a consequence of adaptation to 24 h environmental fluctuations, leading to convergent evolution across different kingdoms of life [1]
Gene expression oscillations of circadian clock genes in this master pacemaker have been shown to dissociate after perturbations of the system such as light pulses and jet-lag
Surrogate data analysis suggests a dissociation of Per1 and Bmal1 dynamics at the single cell level

Summary

Introduction

Circadian clocks are omnipresent in almost all living organisms as a consequence of adaptation to 24 h environmental fluctuations, leading to convergent evolution across different kingdoms of life [1]. Heterodimers of CLOCK and BMAL1 proteins enhance the transcription of Per and Clock genes by binding to their E-box promoter elements The products of these genes, PER and CLOCK proteins, antagonize the activatory effects of the CLOCK-BMAL1 heterodimers and close the delayed negative feedback loop. This feedback loop will be hereinafter referred to as the Per loop. Like Per and Cry genes, RevErb and Ror are transcriptionally activated by heterodimers of CLOCK and BMAL1 It has been shown by computational modeling [5] and confirmed by double-knockouts [6] that this loop plays an essential role in the rhythm generation. It has been proposed that interlocking of such multiple loops contributes to the flexibility and robustness of the circadian system [7,8,9,10]

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