Desynchronization of Noisy Multi-cellular Clocks Underlies the Population-level Singularity Behavior of Mammalian Circadian Clock

摘要

The singularity behavior of circadian clocks defined as the suppression of circadian oscillation by critical perturbation is one of the intriguing dynamical properties of circadian rhythms. Although the singularity behaviors have been observed in various organisms, its mechanism has not yet been elucidated, because the hierarchical structure of multi-cell-level circadian clocks exists behind the organism-level circadian rhythm. In vitro light-responsible circadian system is indispensable for extracting the underlying mechanism of the singularity behavior behind the hierarchical structure of multi-cell organisms. To obtain such in vitro system, we synthetically constructed light-responsible mammalian clock cells by exogenously introducing a photo-responsible receptor. By using this synthetic system and population-level high-throughput promoter activity assay, we found that a light pulse with critical timing and strength can induce population-level singularity behavior of the light-responsible mammalian clock cells. Subsequent single-cell measurement revealed that desynchronization of multi-cellular clocks underlies the population-level singularity. A mathematical model consistently explains our population-level and single-cell-level experimental data, and also demonstrates that the synchronization and desynchronization of cellular clocks is the underlying mechanism of population-level response of circadian clocks to external perturbation. In addition, our model suggests that fluctuation in single-cell-level behavior of the clock cells is the key determinant of the observable singularity behavior.