Evolution of the repression mechanisms in circadian clocks

Jonathan Tyler,Jay Dunlap,Yining Lu,Daniel B Forger

doi:10.1186/s13059-021-02571-0

Jonathan Tyler, Jay Dunlap + Show 2 more

Open Access

https://doi.org/10.1186/s13059-021-02571-0

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Abstract

BackgroundCircadian (daily) timekeeping is essential to the survival of many organisms. An integral part of all circadian timekeeping systems is negative feedback between an activator and repressor. However, the role of this feedback varies widely between lower and higher organisms.ResultsHere, we study repression mechanisms in the cyanobacterial and eukaryotic clocks through mathematical modeling and systems analysis. We find a common mathematical model that describes the mechanism by which organisms generate rhythms; however, transcription’s role in this has diverged. In cyanobacteria, protein sequestration and phosphorylation generate and regulate rhythms while transcription regulation keeps proteins in proper stoichiometric balance. Based on recent experimental work, we propose a repressor phospholock mechanism that models the negative feedback through transcription in clocks of higher organisms. Interestingly, this model, when coupled with activator phosphorylation, allows for oscillations over a wide range of protein stoichiometries, thereby reconciling the negative feedback mechanism in Neurospora with that in mammals and cyanobacteria.ConclusionsTaken together, these results paint a picture of how circadian timekeeping may have evolved.

Highlights

Circadian timekeeping is essential to the survival of many organisms
A novel “Phospholock” model of the eukaryotic clock In light of recent results that reveal a complex interplay between binding of the activator and repressor as well as the timing and ordering of phosphorylation of the repressors [23,24,25], we introduce an extension of System (M) for higher-order eukaryotes that incorporates additional phosphorylation of the repressor after binding to the activator
Additional activator phosphorylation in the phospholock model allows for wider stoichiometric ratios While System (E) represents the mechanisms of the circadian clock in Drosophila and mammals, we investigate the mechanism in Neurospora

Summary

Introduction

An integral part of all circadian timekeeping systems is negative feedback between an activator and repressor. Results: Here, we study repression mechanisms in the cyanobacterial and eukaryotic clocks through mathematical modeling and systems analysis. We find a common mathematical model that describes the mechanism by which organisms generate rhythms; transcription’s role in this has diverged. Based on recent experimental work, we propose a repressor phospholock mechanism that models the negative feedback through transcription in clocks of higher organisms. This model, when coupled with activator phosphorylation, allows for oscillations over a wide range of protein stoichiometries, thereby reconciling the negative feedback mechanism in Neurospora with that in mammals and cyanobacteria. Eukaryotic organisms produce the required negative feedback through transcriptional activation of a repressor that, after a sufficient amount of repressor is present, inhibits the activator from further promoting transcription

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