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

PLoS Comput Biol. 2020 Sep 3;16(9):e1007740. doi: 10.1371/journal.pcbi.1007740. eCollection 2020 Sep.

Abstract

The circadian clock is a complex system that plays many important roles in most organisms. Previously, many mathematical models have been used to sharpen our understanding of the Arabidopsis clock, which brought to light the roles of each transcriptional and post-translational regulations. However, the presence of both regulations, instead of either transcription or post-translation, raised curiosity of whether the combination of these two regulations is important for the clock's system. In this study, we built a series of simplified oscillators with different regulations to study the importance of post-translational regulation (specifically, 26S proteasome degradation) in the clock system. We found that a simple transcriptional-based oscillator can already generate sustained oscillation, but the oscillation can be easily destroyed in the presence of transcriptional leakage. Coupling post-translational control with transcriptional-based oscillator in a feed-forward loop will greatly improve the robustness of the oscillator in the presence of basal leakage. Using these general models, we were able to replicate the increased variability observed in the E3 ligase mutant for both plant and mammalian clocks. With this insight, we also predict a plausible regulator of several E3 ligase genes in the plant's clock. Thus, our results provide insights into and the plausible importance in coupling transcription and post-translation controls in the clock system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arabidopsis / genetics
  • Arabidopsis / physiology
  • Arabidopsis Proteins / genetics
  • Arabidopsis Proteins / metabolism
  • Circadian Clocks / genetics*
  • Computational Biology
  • Feedback, Physiological
  • Gene Expression Regulation, Plant / genetics
  • Models, Biological*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Processing, Post-Translational / genetics*
  • Transcription, Genetic / genetics*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Arabidopsis Proteins
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease

Grants and funding

We acknowledge support from Academia Sinica through the Investigator Award (AS-IA-106-M01), the Ministry of Sciences and Technology of Taiwan (grant no. MOST 105-2113-M-001 -009 -MY4), and a joint research grant from National Taiwan University and Academia Sinica (NTU-AS-106R104517) for support of this research work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.