Basal leakage in oscillation: coupled transcriptional and translational control using feed-forward loops

Abstract

22The circadian clock is a complex system that plays many important roles in most organisms.23 Previously, many mathematical models have been used to sharpen our understanding of 24 the Arabidopsis clock. However, these models are mostly dependent on transcriptional 25 regulation, and the importance of post-translational regulation is still rarely discussed from 26 theoretical aspects. In this study, we built a series of simplified oscillators with different 27 regulations to study the importance of post-translational regulation (specifically, 26S 28 proteasome degradation) in the clock system. We found that a simple transcriptional-based 29 oscillator can already generate sustained oscillation, but the oscillation can be easily 30 destroyed in the presence of transcriptional leakage. Coupling post-translational control 31 with transcriptional-based oscillator in a feed-forward loop will greatly improve the 32 robustness of the oscillator in the presence of basal leakage. Using these general models, 33 we were able to replicate the increased variability observed in the E3 ligase mutant for both 34 plant and mammalian clocks. With this insight, we also predict a plausible regulator of 35 several E3 ligase genes in the plant's clock. Thus, our results provide insights into and the 36 plausible importance in coupling transcription and post-translation controls in the clock 37 system. 38 39 Keywords biological clock, 26S-proteasome degradation, feed-forward loop, mathematical 40 model, system biology 41 Author summary 42For circadian clocks, several current models had successfully captured the essential 43 dynamic behavior of the clock system mainly with transcriptional regulation. Previous 44 studies have shown that the 26s (1, 2) proteasome degradation controls are important in 45 maintaining the stability of circadian rhythms. However, how the loss-of-function or over-46 expression mutant of this targeted degradations lead to unstable oscillation is still unclear.47 In this work, we investigate the importance of coupled transcriptional and post-48 translational feedback loop in the circadian oscillator. With general models our study 49 indicate that the unstable behavior of degradation mutants could be caused by the increase 50 in the basal level of the clock genes. We found that coupling a non-linear degradation 51 control into this transcriptional based oscillator using feed-forward loop improves the 52 robustness of the oscillator. Using this finding, we further predict some plausible regulators 53 of Arabidopsis's E3 ligase protein such as COP1 and SINAT5. Hence, our results provide 54 insights on the importance of coupling transcription and post-translation controls in the 55 clock system. 56The circadian clock is an endogenous time-keeping mechanism in cells that 57 anticipates daily changes in the environment (3-6). It controls the daily rhythm of many 58 biological processes (7-9) and disruption of the clock has been associated with many 59 disadvantageous traits (10-13). Like many eukaryotes, in the Arabi...