An Inactivation Switch Enables Rhythms in a Neurospora Clock Model

Upadhyay, Abhishek; Brunner, Michael; Herzel, Hanspeter

doi:10.3390/ijms20122985

Cited by 16 publications

(19 citation statements)

References 86 publications

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“…Bifurcation analyses on a manifold of clock models have shown that parameter changes can lead to transitions between stable equilibrium points and periodic limit cycle oscillations [ 41 , 74 , 75 ]. In this study, we have found that more complex bifurcations, such as subcritical Hopf bifurcations, period-doubling cascades that lead to chaos or bifurcations that result in toroidal oscillations, can occur in simple, yet comprehensive models of the mammalian circadian clock.…”

Section: Discussionmentioning

confidence: 99%

Nonlinear phenomena in models of the circadian clock

Soest

Olmo

Schmal

et al. 2020

J. R. Soc. Interface.

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The mammalian circadian clock is well-known to be important for our sleep–wake cycles, as well as other daily rhythms such as temperature regulation, hormone release or feeding–fasting cycles. Under normal conditions, these daily cyclic events follow 24 h limit cycle oscillations, but under some circumstances, more complex nonlinear phenomena, such as the emergence of chaos, or the splitting of physiological dynamics into oscillations with two different periods, can be observed. These nonlinear events have been described at the organismic and tissue level, but whether they occur at the cellular level is still unknown. Our results show that period-doubling, chaos and splitting appear in different models of the mammalian circadian clock with interlocked feedback loops and in the absence of external forcing. We find that changes in the degradation of clock genes and proteins greatly alter the dynamics of the system and can induce complex nonlinear events. Our findings highlight the role of degradation rates in determining the oscillatory behaviour of clock components, and can contribute to the understanding of molecular mechanisms of circadian dysregulation.

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Section: Discussionmentioning

confidence: 99%

Nonlinear phenomena in models of the circadian clock

Soest

Olmo

Schmal

et al. 2020

J. R. Soc. Interface.

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“…We emphasize, that our focus on multiple random phosphorylations neglects other essentials of the TTFL modeled in detail elsewhere 26,80,90,91 . Nevertheless, delayed switch-like behavior due to slow random multiple phosphorylation seems to be central element in circadian rhythm generation.…”

Section: Discussionmentioning

confidence: 99%

Multiple random phosphorylations in clock proteins provide long delays and switches

Upadhyay

Marzoll

Diernfellner

et al. 2020

Sci Rep

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Theory predicts that self-sustained oscillations require robust delays and nonlinearities (ultrasensitivity). Delayed negative feedback loops with switch-like inhibition of transcription constitute the core of eukaryotic circadian clocks. The kinetics of core clock proteins such as PER2 in mammals and FRQ in Neurospora crassa is governed by multiple phosphorylations. We investigate how multiple, slow and random phosphorylations control delay and molecular switches. We model phosphorylations of intrinsically disordered clock proteins (IDPs) using conceptual models of sequential and distributive phosphorylations. Our models help to understand the underlying mechanisms leading to delays and ultrasensitivity. The model shows temporal and steady state switches for the free kinase and the phosphoprotein. We show that random phosphorylations and sequestration mechanisms allow high Hill coefficients required for self-sustained oscillations.

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“…We emphasize, that our focus on multiple random phosphorylations neglects other essentials of the transcriptional-translational feedback loop (TTFL) modeled in detail elsewhere [26,[75][76][77][78]. Nevertheless, delayed switch-like behavior due to slow random multiple phosphorylation seems to be central element in circadian rhythm generation.…”

Section: Discussionmentioning

confidence: 99%

Multiple random phosphorylations in clock proteins provide long delays and switches

Upadhyay

Marzoll

Diernfellner

et al. 2020

Preprint

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AbstractTheory predicts that self-sustained oscillations require robust delays and nonlinearities (ultrasensitivity). Delayed negative feedback loops with switch-like inhibition of transcription constitute the core of eukaryotic circadian clock. The kinetics of core clock proteins such as PER2 in mammals and FRQ in Neurospora crassa is governed by multiple phosphorylations. We investigate how multiple, slow and random phosphorylations control delay and molecular switches. We model phosphorylations of intrinsically disordered clock proteins (IDPs) using conceptual models of sequential and distributive phosphorylations. Our models help to understand the underlying mechanisms leading to delays and ultrasensitivity. The model shows temporal and steady state switches for the free kinase and the phosphoprotein. We show that random phosphorylations and sequestration mechanisms allow high Hill coefficients required for self-sustained oscillations.

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An Inactivation Switch Enables Rhythms in a Neurospora Clock Model

Cited by 16 publications

References 86 publications

Nonlinear phenomena in models of the circadian clock

Nonlinear phenomena in models of the circadian clock

Multiple random phosphorylations in clock proteins provide long delays and switches

Multiple random phosphorylations in clock proteins provide long delays and switches

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