title: Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator.
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.
authors.affiliation: Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Pett
authors.affiliation: Center for Functional Genomics and Biochips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Anja
authors.initials: A
authors.lastname: Korenčič
authors.affiliation: Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Wesener
authors.affiliation: Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Kramer
authors.affiliation: Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Herzel
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000235:genetics* / Q000502:physiology; D019295:Computational Biology; D025461:Feedback, Physiological; D053263:Gene Regulatory Networks / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008957:Models, Genetic