Modelling of circadian rhythms in Drosophila incorporating the interlocked PER/TIM and VRI/PDP1 feedback loops

Xie, Zhi; Kulasiri, Don

doi:10.1016/j.jtbi.2006.10.028

Cited by 35 publications

(57 citation statements)

References 58 publications

(94 reference statements)

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“…For example, these models have not incorporated (1) the six experimentally found TFs (PER, TIM, CLK, CYC, VRI and PDP1) and their roles, (2) functionalities of E-boxes of tim, per, vri and pdp1 genes and V/P box in clk gene in transcriptional and translational stages of gene expression, and (3) interlocked nature of the PER/TIM and VRI/PDP1 feedback loops. We have developed a new model which includes these missing aspects of biological reality extending the previous work [55], and explains some of the experimental observations in meaningful manner.…”

Section: Mathematical Models Of the Circadian Clock In Drosophilamentioning

confidence: 97%

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Modelling Circadian Rhythms in Drosophila and Investigation of VRI and PDP1 Feedback Loops Using a New Mathematical Model

Kulasiri

Xie

2008

Math. Model. Nat. Phenom.

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Abstract. We present a brief review of molecular biological basis and mathematical modelling of circadian rhythms in Drosophila. We discuss pertinent aspects of a new model that incorporates the transcriptional feedback loops revealed so far in the network of the circadian clock (PER/TIM and VRI/PDP1 loops). Conventional Hill functions are not used to describe the regulation of genes, instead the explicit reactions of binding and unbinding processes of transcription factors to promoters are probabilistically modelled. The model is described by a set of ordinary differential equations, and the parameters are estimated from the in vitro experimental data of the clocks' components. The model is robust over a wide range of parameter variations. Through the sensitivity analysis of the model, roles of VRI and PDP1 feedback loops are investigated, and it is proposed that they increase the robustness of the clock.

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Section: Mathematical Models Of the Circadian Clock In Drosophilamentioning

confidence: 97%

“…We summarise the pertinent aspects of our model in this section and for details refer to [55]; the mathematical model follows the conceptual model shown in Figure 2 . The core structure of the model is similar to the model proposed by Cyran et al [8], as schematised in Figure 1.…”

Section: A New Modelmentioning

confidence: 99%

Modelling Circadian Rhythms in Drosophila and Investigation of VRI and PDP1 Feedback Loops Using a New Mathematical Model

Kulasiri

Xie

2008

Math. Model. Nat. Phenom.

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“…The parameters in these models have a physical interpretation: they denote synthesis or degradation rates, binding affinities, transport rates, etc. Detailed models for circadian clocks are now available for mammals [47][48][49][50], Neurospora [51,52], Drosophila [53][54][55][56][57], and Arabidopsis [58][59][60][61].…”

Section: From Scheme To Equationsmentioning

confidence: 99%

Modeling circadian clocks: From equations to oscillations

Gonze¹

2011

Open Life Sciences

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Circadian rhythms are generated at the cellular level by a small but tightly regulated genetic network. In higher eukaryotes, interlocked transcriptional-translational feedback loops form the core of this network, which ensures the activation of the right genes (proteins) at the right time of the day. Understanding how such a complex molecular network can generate robust, self-sustained oscillations and accurately responds to signals from the environment (such as light and temperature) is greatly helped by mathematical modeling. In the present paper we review some mathematical models for circadian clocks, ranging from abstract, phenomenological models to the most detailed molecular models. We explain how the equations are derived, highlighting the challenges for the modelers, and how the models are analyzed. We show how to compute bifurcation diagrams, entrainment, and phase response curves. In the subsequent paper, we discuss, through a selection of examples, how modeling efforts have contributed to a better understanding of the dynamics of the circadian regulatory network.

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“…The initial aim of this modeling approach was generally to introduce in the system a delay that favors the appearance of oscillations. Now many recent models pay more attention to the transcriptional or other post-translational regulations without integrating explicitly any phosphorylation [87,88]. The recent discovery of the differential functions of CKI or DBT will certainly incline modelers to reconsider the importance of the phosphorylations in the regulatory mechanism of the Drosophila circadian clock and lead them to integrate multiple roles of these phosphorylations in their models.…”

Section: The Drosophila Circadian Clockmentioning

confidence: 99%

Circadian clocks and phosphorylation: Insights from computational modeling

Leloup

2009

Open Life Sciences

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Circadian clocks are based on a molecular mechanism regulated at the transcriptional, translational and post-translational levels.Recent experimental data unravel a complex role of the phosphorylations in these clocks. In mammals, several kinases play differential roles in the regulation of circadian rhythmicity. A dysfunction in the phosphorylation of one clock protein could lead to sleep disorders such as the Familial Advanced Sleep Phase Disorder, FASPS. Moreover, several drugs are targeting kinases of the circadian clocks and can be used in cancer chronotherapy or to treat mood disorders. In Drosophila, recent experimental observations also revealed a complex role of the phosphorylations. Because of its high degree of homology with mammals, the Drosophila system is of particular interest. In the circadian clock of cyanobacteria, an atypical regulatory mechanism is based only on three clock proteins (KaiA, KaiB, KaiC) and ATP and is sufficient to produce robust temperature-compensated circadian oscillations of KaiC phosphorylation. This review will show how computational modeling has become a powerful and useful tool in investigating the regulatory mechanism of circadian clocks, but also how models can give rise to testable predictions or reveal unexpected results.

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Modelling of circadian rhythms in Drosophila incorporating the interlocked PER/TIM and VRI/PDP1 feedback loops

Abstract: The deficiency between the simulated mRNA levels and experimental observations in per 01 , tim 01 and clk Jrk mutants suggests some difference on the part of the model from reality.

Cited by 35 publications

References 58 publications

Modelling Circadian Rhythms in Drosophila and Investigation of VRI and PDP1 Feedback Loops Using a New Mathematical Model

Modelling Circadian Rhythms in Drosophila and Investigation of VRI and PDP1 Feedback Loops Using a New Mathematical Model

Modeling circadian clocks: From equations to oscillations

Circadian clocks and phosphorylation: Insights from computational modeling

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