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Modeling the effects of cell cycle M-phase transcriptional inhibition on circadian oscillation.

Kang B, Li YY, Chang X, Liu L, Li YX - PLoS Comput. Biol. (2008)

Bottom Line: The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light-dark cycle does.This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter.This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Systems Biology [corrected] Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
Circadian clocks are endogenous time-keeping systems that temporally organize biological processes. Gating of cell cycle events by a circadian clock is a universal observation that is currently considered a mechanism serving to protect DNA from diurnal exposure to ultraviolet radiation or other mutagens. In this study, we put forward another possibility: that such gating helps to insulate the circadian clock from perturbations induced by transcriptional inhibition during the M phase of the cell cycle. We introduced a periodic pulse of transcriptional inhibition into a previously published mammalian circadian model and simulated the behavior of the modified model under both constant darkness and light-dark cycle conditions. The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light-dark cycle does. At equilibrium states, a transcriptional inhibition pulse of certain periods was always locked close to certain circadian phases where inhibition on Per and Bmal1 mRNA synthesis was most balanced. In a light-dark cycle condition, inhibitions imposed at different parts of a circadian period induced different degrees of perturbation to the circadian clock. When imposed at the middle- or late-night phase, the transcriptional inhibition cycle induced the least perturbations to the circadian clock. The late-night time window of least perturbation overlapped with the experimentally observed time window, where mitosis is most frequent. This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter. This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of cell cycle.

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Steady state circadian phases of cell cycle M-phase.The cell cycle M-phase is introduced into the mammalian circadian model as transcriptional inhibition cycles of different periods. For each period, transcriptional inhibitions are imposed at various circadian phases with an interval of 30 minutes. The resulting models are simulated. Simulation data are sampled at equilibrium state and the circadian phases where cell cycle M-phase is located are calculated for each simulation. The calculated phases are combined and plotted against transcriptional inhibition periods.
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pcbi-1000019-g003: Steady state circadian phases of cell cycle M-phase.The cell cycle M-phase is introduced into the mammalian circadian model as transcriptional inhibition cycles of different periods. For each period, transcriptional inhibitions are imposed at various circadian phases with an interval of 30 minutes. The resulting models are simulated. Simulation data are sampled at equilibrium state and the circadian phases where cell cycle M-phase is located are calculated for each simulation. The calculated phases are combined and plotted against transcriptional inhibition periods.

Mentions: Next, we assessed the distribution of cell cycle M-phase (transcriptional inhibition pulse) on the circadian phase of the coupled system at equilibrium entrainment. To this end, the phases of the circadian cycles where inhibition pulses occurred were determined at equilibrium of every simulation and plotted against the cell cycle periods. As shown in Figure 3, patterns similar to those in Figure 2 emerge. At cell cycle periods close to half of 24 h, 24 h or twice 24 h, where period entrainment occurs, inhibition pulses were also entrained to specific circadian phases. At other phases of the period, no such phase entrainment could be detected.


Modeling the effects of cell cycle M-phase transcriptional inhibition on circadian oscillation.

Kang B, Li YY, Chang X, Liu L, Li YX - PLoS Comput. Biol. (2008)

Steady state circadian phases of cell cycle M-phase.The cell cycle M-phase is introduced into the mammalian circadian model as transcriptional inhibition cycles of different periods. For each period, transcriptional inhibitions are imposed at various circadian phases with an interval of 30 minutes. The resulting models are simulated. Simulation data are sampled at equilibrium state and the circadian phases where cell cycle M-phase is located are calculated for each simulation. The calculated phases are combined and plotted against transcriptional inhibition periods.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2267494&req=5

pcbi-1000019-g003: Steady state circadian phases of cell cycle M-phase.The cell cycle M-phase is introduced into the mammalian circadian model as transcriptional inhibition cycles of different periods. For each period, transcriptional inhibitions are imposed at various circadian phases with an interval of 30 minutes. The resulting models are simulated. Simulation data are sampled at equilibrium state and the circadian phases where cell cycle M-phase is located are calculated for each simulation. The calculated phases are combined and plotted against transcriptional inhibition periods.
Mentions: Next, we assessed the distribution of cell cycle M-phase (transcriptional inhibition pulse) on the circadian phase of the coupled system at equilibrium entrainment. To this end, the phases of the circadian cycles where inhibition pulses occurred were determined at equilibrium of every simulation and plotted against the cell cycle periods. As shown in Figure 3, patterns similar to those in Figure 2 emerge. At cell cycle periods close to half of 24 h, 24 h or twice 24 h, where period entrainment occurs, inhibition pulses were also entrained to specific circadian phases. At other phases of the period, no such phase entrainment could be detected.

Bottom Line: The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light-dark cycle does.This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter.This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Systems Biology [corrected] Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
Circadian clocks are endogenous time-keeping systems that temporally organize biological processes. Gating of cell cycle events by a circadian clock is a universal observation that is currently considered a mechanism serving to protect DNA from diurnal exposure to ultraviolet radiation or other mutagens. In this study, we put forward another possibility: that such gating helps to insulate the circadian clock from perturbations induced by transcriptional inhibition during the M phase of the cell cycle. We introduced a periodic pulse of transcriptional inhibition into a previously published mammalian circadian model and simulated the behavior of the modified model under both constant darkness and light-dark cycle conditions. The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light-dark cycle does. At equilibrium states, a transcriptional inhibition pulse of certain periods was always locked close to certain circadian phases where inhibition on Per and Bmal1 mRNA synthesis was most balanced. In a light-dark cycle condition, inhibitions imposed at different parts of a circadian period induced different degrees of perturbation to the circadian clock. When imposed at the middle- or late-night phase, the transcriptional inhibition cycle induced the least perturbations to the circadian clock. The late-night time window of least perturbation overlapped with the experimentally observed time window, where mitosis is most frequent. This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter. This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of cell cycle.

Show MeSH
Related in: MedlinePlus