PT  - JOURNAL ARTICLE
AU  - Christoph Schmal
AU  - Daisuke Ono
AU  - Jihwan Myung
AU  - J. Patrick Pett
AU  - Sato Honma
AU  - Ken-Ichi Honma
AU  - Hanspeter Herzel
AU  - Isao T. Tokuda
TI  - Weak Coupling Between Intracellular Feedback Loops Explains Dissociation of Clock Gene Dynamics
AID  - 10.1101/542852
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 542852
4099  - http://biorxiv.org/content/early/2019/02/06/542852.short
4100  - http://biorxiv.org/content/early/2019/02/06/542852.full
AB  - Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described in recent experimental studies that applied various perturbations such as slice preparations, light pulses, jet-lag, and culture medium exchange. In this paper, we provide evidence that this "presumably transient" dissociation of circadian gene expression oscillations may occur at the single-cell level. Conceptual and detailed mechanistic mathematical modeling suggests that such dissociation is due to a weak interaction between multiple feedback loops present within a single cell. The dissociable loops provide insights into underlying mechanisms and general design principles of the molecular circadian clock.