Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator

PLoS Comput Biol. 2016 Dec 12;12(12):e1005266. doi: 10.1371/journal.pcbi.1005266. eCollection 2016 Dec.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circadian Clocks / genetics*
  • Circadian Clocks / physiology
  • Computational Biology
  • Feedback, Physiological
  • Gene Regulatory Networks / genetics*
  • Gene Regulatory Networks / physiology
  • Mice
  • Models, Genetic*

Grant support

This work was supported by grants from Deutsche Forschungsgemeinschaft (SPP 1395, GRK 1772, TRR 186) and BMBF (Computational Neuroscience). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.