Abstract
The circadian clock controls many physiological processes in higher plants and causes a large fraction of the genome to be expressed with a 24h rhythm. The transcripts encoding the RNA-binding proteins AtGRP7 (Arabidopsis thaliana Glycine Rich Protein 7) and AtGRP8 oscillate with evening peaks. The circadian clock components CCA1 and LHY negatively affect AtGRP7 expression at the level of transcription. AtGRP7 and AtGRP8, in turn, negatively auto-regulate and reciprocally cross-regulate post-transcriptionally: high protein levels promote the generation of an alternative splice form that is rapidly degraded. This clock-regulated feedback loop has been proposed to act as a molecular slave oscillator in clock output. While mathematical models describing the circadian core oscillator in Arabidopsis thaliana were introduced recently, we propose here the first model of a circadian slave oscillator. We define the slave oscillator in terms of ordinary differential equations and identify the model's parameters by an optimization procedure based on experimental results. The model successfully reproduces the pertinent experimental findings such as waveforms, phases, and half-lives of the time-dependent concentrations. Furthermore, we obtain insights into possible mechanisms underlying the observed experimental dynamics: the negative auto-regulation and reciprocal cross-regulation via alternative splicing could be responsible for the sharply peaking waveforms of the AtGRP7 and AtGRP8 mRNA. Moreover, our results suggest that the AtGRP8 transcript oscillations are subordinated to those of AtGRP7 due to a higher impact of AtGRP7 protein on alternative splicing of its own and of the AtGRP8 pre-mRNA compared to the impact of AtGRP8 protein. Importantly, a bifurcation analysis provides theoretical evidence that the slave oscillator could be a toggle switch, arising from the reciprocal cross-regulation at the post-transcriptional level. In view of this, transcriptional repression of AtGRP7 and AtGRP8 by LHY and CCA1 induces oscillations of the toggle switch, leading to the observed high-amplitude oscillations of AtGRP7 mRNA.
Highlights
Circadian clocks are endogenous timekeepers that can be found among all taxa of life [1,2,3]
In order to investigate the effect of changes in the LATE ELONGATED HYPOCOTYL (LHY)/CCA1 protein concentrations PL(t), and whether our driven AtGRP7-AtGRP8 slave oscillator shows robust amplitudes for varying PgLeneric(t) as well, we examined the behavior of the system for different amplitudes A0 and waveforms E of the core oscillator while keeping Tgeneric~24h and b~0:035 constant
We assumed that the slave oscillator gains input from the circadian core oscillator via transcriptional repression by the LHY/CCA1 proteins
Summary
Circadian clocks are endogenous timekeepers that can be found among all taxa of life [1,2,3]. Entrainment by environmental signals such as light and temperature can synchronize the clock to the period of the Earth’s rotation Such a clockwork may confer a higher fitness to an organism as it allows to anticipate daily cycles of light and temperature in a spinning world [4,5]. The assumed circadian clock architecture was extended in successive steps [8,9,10,11] from this simple design to the idea of a clockwork that has a repressilator-like architecture at its core [13] In this recent picture a ‘‘morning loop’’ consists of the morningexpressed genes LHY/CCA1 that activate the transcription of the PSEUDO RESPONSE REGULATORS 9, 7 and 5 (PRR9, PRR7 and PRR5) which in turn inhibit the transcription of LHY/CCA1. The circadian clock affects many physiological processes in Arabidopsis thaliana, including the oscillation of free cytosolic
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