Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle

Circadian rhythms and cell cycle oscillations are both fundamental to cellular function. These two oscillatory systems are known to interact, yet their precise coordination remains unclear. While some studies have shown physical interactions between circadian clock proteins and cell cycle regulators, the functional consequences of this coupling are not fully understood. At the tissue level, synchronized cell division occurs daily, but the mechanisms linking this to single-cell behavior are unknown. Prior research has established that circadian clocks influence cell cycle timing, but the extent of this influence at the population level is uncertain. No prior work has resolved how single-cell phase locking could lead to tissue-level synchronization. This gap motivated the current investigation into how circadian clocks and cell cycles interact in mouse fibroblasts. The study aims to clarify how these oscillators synchronize and what this means for cellular coordination.

This study investigates how the mammalian circadian clock and cell cycle oscillators synchronize at the single-cell level. The goal is to determine whether phase locking occurs between these systems and how it affects population-level rhythms. The researchers aim to uncover the mechanisms that allow the two oscillators to maintain a common frequency despite individual cell variability. By using live cell imaging and mathematical modeling, they seek to identify distinct oscillatory states and transitions between them. The study also explores how dexamethasone-induced synchronization influences clock states. Understanding these interactions could provide insights into how circadian disruptions affect cell division. The results may help explain the biological relevance of clock-cell cycle coupling in mammals.

The researchers used multispectral imaging of live mouse fibroblasts to track both circadian clock and cell cycle oscillations. They applied computational methods to analyze the temporal coordination of these processes. Mathematical modeling was used to simulate and predict phase locking behavior. The study focused on unsynchronized cells to observe natural oscillatory patterns. Dexamethasone was used to synchronize cells and reveal additional clock states. The team monitored transitions between low-period and high-period clock states after synchronization. They analyzed how phase locking affects population-level rhythms. The combination of live imaging and modeling allowed them to test hypotheses about oscillator coupling.

The study found that in unsynchronized cells, the circadian clock and cell cycle oscillators phase lock in a 1:1 ratio. This phase locking ensures that both oscillators maintain a synchronized frequency in an expanding cell population. Dexamethasone synchronization revealed additional clock states with higher periods. These states coexist with the low-period phase-locked state. Transitions to these higher-period states occur after dexamethasone treatment. The phase locking mechanism allows single-cell rhythms to align with the circadian clock. This coordination is robust and persists despite cell cycle variability. The findings suggest that phase locking is a key mechanism for synchronizing cell division at the tissue level.

The results suggest that phase locking between the circadian clock and cell cycle oscillators is a robust mechanism for synchronizing cell division. This synchronization occurs at the single-cell level and leads to coordinated rhythms in an expanding population. Dexamethasone synchronization reveals multiple coexisting clock states with distinct periods. These findings imply that the circadian clock can influence cell cycle timing in multiple ways. The authors propose that phase locking is essential for maintaining tissue-level rhythms. The study highlights the importance of circadian-cell cycle interactions in cellular coordination. Disordered circadian function may disrupt this coordination, contributing to disease. The results support the idea that clock-cell cycle coupling is biologically relevant.