Kernel Architecture of the Genetic Circuitry of the Arabidopsis Circadian System

TL;DR

This study uncovers the core regulatory structure of the Arabidopsis circadian clock, highlighting the predominance of inhibitory interactions that shape sharply peaked gene expression profiles and are essential for maintaining rhythmicity.

Contribution

It identifies the minimal set of regulatory interactions, called the kernel, necessary for circadian rhythms and reveals a predominance of inhibitory interactions shaping the clock's dynamics.

Findings

At least half of the regulatory interactions are essential for circadian expression.

The kernel structure consists of four interlocked negative feedback loops.

Inhibitory interactions dominate, leading to cuspidate waveforms.

Abstract

A wide range of organisms features molecular machines, circadian clocks, which generate endogenous oscillations with ~24 h periodicity and thereby synchronize biological processes to diurnal environmental fluctuations. Recently, it has become clear that plants harbor more complex gene regulatory circuits within the core circadian clocks than other organisms, inspiring a fundamental question: are all these regulatory interactions between clock genes equally crucial for the establishment and maintenance of circadian rhythms? Our mechanistic simulation for Arabidopsis thaliana demonstrates that at least half of the total regulatory interactions must be present to express the circadian molecular profiles observed in wild-type plants. A set of those essential interactions is called herein a kernel of the circadian system. The kernel structure unbiasedly reveals four interlocked negative feedback loops contributing to circadian rhythms, and three feedback loops among them drive the autonomous oscillation itself. Strikingly, the kernel structure, as well as the whole clock circuitry, is overwhelmingly composed of inhibitory, rather than activating, interactions between genes. We found that this tendency underlies plant circadian molecular profiles which often exhibit sharply-shaped, cuspidate waveforms. Through the generation of these cuspidate profiles, inhibitory interactions may facilitate the global coordination of temporally-distant clock events that are markedly peaked at very specific times of day. Our systematic approach resulting in experimentally-testable predictions provides insights into a design principle of biological clockwork, with implications for synthetic biology.