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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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Per and Bmal1 mRNA synthesis rate curves.
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pcbi-1000019-g005: Per and Bmal1 mRNA synthesis rate curves.

Mentions: If inhibition occurs at circadian phases where synthesis of clock gene mRNAs are actively expressed, circadian rhythms will possibly be perturbed. However, if inhibition occurs at circadian phases either without clock gene mRNA expression or with balanced synthesis of two antagonistic genes, there will be no or minimal effect on the circadian clock. Figure 5 displays the mRNA synthesis rates of clock genes across the circadian period. Since the synthesis of Per mRNAs (NM_011065.3, NM_011066.3, NM_011067.2) and Cry mRNAs (NM_007771.3, NM_009963.3) are roughly in-phase, only the synthesis rates of Per mRNA and Bmal mRNA (NM_007489.3) are displayed in Figure 5. The synthesis rate curves of the two mRNA molecules intersect at two points across the circadian period. These two intersection points are close to those two locking circadian phases where inhibition pulses occurred at equilibrium, as shown in Figure 4. Since the syntheses of the Per and Bmal1 mRNAs oscillate in anti-phase, transcriptional inhibition at any point other than these two intersection points will lead to unbalanced inhibition, e.g. the less the inhibition of one gene, the greater that of the other, thus resulting in larger system perturbations. On the other hand, inhibition at these two points results in equal inhibition of both molecules and thus the least perturbation of the circadian clock. This would explain why entrainment of the circadian clock by the cell division cycle always occurs at these two phase points.


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)

Per and Bmal1 mRNA synthesis rate curves.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000019-g005: Per and Bmal1 mRNA synthesis rate curves.
Mentions: If inhibition occurs at circadian phases where synthesis of clock gene mRNAs are actively expressed, circadian rhythms will possibly be perturbed. However, if inhibition occurs at circadian phases either without clock gene mRNA expression or with balanced synthesis of two antagonistic genes, there will be no or minimal effect on the circadian clock. Figure 5 displays the mRNA synthesis rates of clock genes across the circadian period. Since the synthesis of Per mRNAs (NM_011065.3, NM_011066.3, NM_011067.2) and Cry mRNAs (NM_007771.3, NM_009963.3) are roughly in-phase, only the synthesis rates of Per mRNA and Bmal mRNA (NM_007489.3) are displayed in Figure 5. The synthesis rate curves of the two mRNA molecules intersect at two points across the circadian period. These two intersection points are close to those two locking circadian phases where inhibition pulses occurred at equilibrium, as shown in Figure 4. Since the syntheses of the Per and Bmal1 mRNAs oscillate in anti-phase, transcriptional inhibition at any point other than these two intersection points will lead to unbalanced inhibition, e.g. the less the inhibition of one gene, the greater that of the other, thus resulting in larger system perturbations. On the other hand, inhibition at these two points results in equal inhibition of both molecules and thus the least perturbation of the circadian clock. This would explain why entrainment of the circadian clock by the cell division cycle always occurs at these two phase points.

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