Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator.

J Patrick Pett,Anja Korenčič,Felix Wesener,Hanspeter Herzel,Achim Kramer,Denis Thieffry

doi:10.1371/journal.pcbi.1005266

Abstract

Mammals evolved an endogenous timing system to coordinate their physiology and behaviour to the 24h period of the solar day. While it is well accepted that circadian rhythms are generated by intracellular transcriptional feedback loops, it is still debated which network motifs are necessary and sufficient for generating self-sustained oscillations. Here, we systematically explore a data-based circadian oscillator model with multiple negative and positive feedback loops and identify a series of three subsequent inhibitions known as “repressilator” as a core element of the mammalian circadian oscillator. The central role of the repressilator motif is consistent with time-resolved ChIP-seq experiments of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts.

Highlights

An autonomous circadian clock controls daily rhythms in physiology and behaviour in a large variety of species
The central role of the repressilator motif is consistent with time-resolved binding data of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts
Circadian rhythms are generated by intracellular transcriptional feedback loops involving cis-regulatory elements such as E-boxes, D-boxes, and ROR-elements (RREs)

Summary

Introduction

An autonomous circadian clock controls daily rhythms in physiology and behaviour in a large variety of species. Such an endogenous timing system has evolved to adapt to the 24h period of the solar day. Circadian rhythms are generated by intracellular transcriptional feedback loops involving cis-regulatory elements such as E-boxes, D-boxes, and ROR-elements (RREs). More than 20 core clock genes assemble a sophisticated gene regulatory network. With multiple negative and positive feedback loops [1]. Given the complexity of this network, we here investigate, which network motifs are necessary and sufficient for generating self-sustained rhythms

Results

Discussion

Conclusion