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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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Entrainment of circadian clock by cell cycles of different periods at constant darkness in the presence of molecular noise.The effects of the cell cycle period on the entrainment in the presence of noise were studied by changing the periods of the square waves imposed onto the circadian model with noise. The periods of the coupled model and the circadian phases (with the peak of Per mRNA as the reference phase) where the troughs of the square wave occurred are determined. The distributions of the resulting circadian periods and the phases of transcriptional inhibition occurrence resulting from one simulation are displayed here.
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pcbi-1000019-g007: Entrainment of circadian clock by cell cycles of different periods at constant darkness in the presence of molecular noise.The effects of the cell cycle period on the entrainment in the presence of noise were studied by changing the periods of the square waves imposed onto the circadian model with noise. The periods of the coupled model and the circadian phases (with the peak of Per mRNA as the reference phase) where the troughs of the square wave occurred are determined. The distributions of the resulting circadian periods and the phases of transcriptional inhibition occurrence resulting from one simulation are displayed here.

Mentions: It has been demonstrated that circadian systems are robust to molecular noise and entrainment of circadian clock by light cycles can occur in the presence of molecular noise [32],[33]. To study the effect of noise on the entrainment of circadian clock by transcriptional inhibition cycles, noises were introduced into the differential equations of the mammalian circadian model. System trajectories of the model were then simulated as above mentioned. Simulation results showed that the model exhibits robust periodic behavior in the presence of noise (see Figure S3) and such periodic behavior remained when either light cycles or transcriptional inhibition cycles is imposed onto the model (data not shown). For transcriptional inhibition cycles, those with periods close to 24 hours are easier to entrain the model, reflected by more focused distribution of the circadian phases where inhibition pulses occur and more centered distributions of entrained circadian periods to values identical to transcription inhibition cycle (Figure 7). When transcriptional inhibition cycles and light cycles of 24 hour are imposed onto the model, inhibition cycles fluctuating with specific phasing relationships with light cycles will induce lest rhythms changes in the model system (Figure 8). These results are compatible with the previous results in the absence of noise.


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)

Entrainment of circadian clock by cell cycles of different periods at constant darkness in the presence of molecular noise.The effects of the cell cycle period on the entrainment in the presence of noise were studied by changing the periods of the square waves imposed onto the circadian model with noise. The periods of the coupled model and the circadian phases (with the peak of Per mRNA as the reference phase) where the troughs of the square wave occurred are determined. The distributions of the resulting circadian periods and the phases of transcriptional inhibition occurrence resulting from one simulation are displayed here.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000019-g007: Entrainment of circadian clock by cell cycles of different periods at constant darkness in the presence of molecular noise.The effects of the cell cycle period on the entrainment in the presence of noise were studied by changing the periods of the square waves imposed onto the circadian model with noise. The periods of the coupled model and the circadian phases (with the peak of Per mRNA as the reference phase) where the troughs of the square wave occurred are determined. The distributions of the resulting circadian periods and the phases of transcriptional inhibition occurrence resulting from one simulation are displayed here.
Mentions: It has been demonstrated that circadian systems are robust to molecular noise and entrainment of circadian clock by light cycles can occur in the presence of molecular noise [32],[33]. To study the effect of noise on the entrainment of circadian clock by transcriptional inhibition cycles, noises were introduced into the differential equations of the mammalian circadian model. System trajectories of the model were then simulated as above mentioned. Simulation results showed that the model exhibits robust periodic behavior in the presence of noise (see Figure S3) and such periodic behavior remained when either light cycles or transcriptional inhibition cycles is imposed onto the model (data not shown). For transcriptional inhibition cycles, those with periods close to 24 hours are easier to entrain the model, reflected by more focused distribution of the circadian phases where inhibition pulses occur and more centered distributions of entrained circadian periods to values identical to transcription inhibition cycle (Figure 7). When transcriptional inhibition cycles and light cycles of 24 hour are imposed onto the model, inhibition cycles fluctuating with specific phasing relationships with light cycles will induce lest rhythms changes in the model system (Figure 8). These results are compatible with the previous results in the absence of noise.

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