Model-based investigation of the circadian clock and cell cycle coupling in mouse embryonic fibroblasts: Prediction of RevErb-α up-regulation during mitosis

Traynard, Pauline; Feillet, Céline; Soliman, Sylvain; Delaunay, Franck; Fages, François

doi:10.1016/j.biosystems.2016.07.003

Cited by 16 publications

(13 citation statements)

References 34 publications

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“…The coupling between the circadian clock and the cell cycle is mediated by several cell cycle proteins such as WEE1 [22], p21 [23], NONO [24], and, as shown here, Cyclin B1. Oppositely, there are indications that the cell cycle may have an effect on the circadian clock, but the mechanism of such a coupling remains unclear [33,34], although a recent study points to the enhancement of REV-ERBα degradation through phosphorylation by CDK1 [25]. Therefore, despite recent evidence for bidirectional coupling between the cell cycle and the circadian clock [27,28], we decided to focus on the situation where the cell cycle is unidirectionally coupled to the circadian clock via CLOCK/BMAL1-mediated induction of Wee1 and Cnnb1 expression.…”

Section: Mathematical Modeling Of Clock/ Bmal1-controlled Cell Cycle mentioning

confidence: 99%

The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1

et al. 2018

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We previously identified a tight bidirectional phase coupling between the circadian clock and the cell cycle. To understand the role of the CLOCK/BMAL1 complex, representing the main positive regulator of the circadian oscillator, we knocked down Bmal1 or Clock in NIH3T33C mouse fibroblasts (carrying fluorescent reporters for clock and cell cycle phase) and analyzed timing of cell division in individual cells and cell populations. Inactivation of Bmal1 resulted in a loss of circadian rhythmicity and a lengthening of the cell cycle, originating from delayed G2/M transition. Subsequent molecular analysis revealed reduced levels of Cyclin B1, an important G2/M regulator, upon suppression of Bmal1 gene expression. In complete agreement with these experimental observations, simulation of Bmal1 knockdown in a computational model for coupled mammalian circadian clock and cell cycle oscillators (now incorporating Cyclin B1 induction by BMAL1) revealed a lengthening of the cell cycle. Similar data were obtained upon knockdown of Clock gene expression. In conclusion, the CLOCK/BMAL1 complex controls cell cycle progression at the level of G2/M transition through regulation of Cyclin B1 expression.

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Section: Mathematical Modeling Of Clock/ Bmal1-controlled Cell Cycle mentioning

confidence: 99%

The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1

et al. 2018

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“…In [112], it served to build a quantitative model of the cell cycle and the circadian clock explaining unexpected observations in embryonic fibroblasts, and make the prediction of an up-regulation of clock-gene Reverb-α during mitosis in those cells.…”

Section: Parameter Search With Temporal Logic Constraintsmentioning

confidence: 99%

A Guided Tour of Artificial Intelligence Research

2020

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Systems Biology aims at elucidating the high-level functions of the cell from their biochemical basis at the molecular level. A lot of work has been done for collecting genomic and post-genomic data, making them available in databases and ontologies, building dynamical models of cell metabolism, signalling, division cycle, apoptosis, and publishing them in model repositories. In this chapter we review different applications of AI to biological systems modelling. We focus on cell processes at the unicellular level which constitutes most of the work achieved in the last two decades in the domain of Systems Biology. We show how rule-based languages and logical methods have played an important role in the study of molecular interaction networks and of their emergent properties responsible for cell behaviours. In particular, we present some results obtained with SAT and Constraint Logic Programming solvers for the static analysis of large interaction networks, with Model-Checking and Evolutionary Algorithms for the analysis and synthesis of dynamical models, and with Machine Learning techniques for the current challenges of infering mechanistic models from temporal data and automating the design of biological experiments.

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“…Thus, in Section 3, we model the CLOCK:BMAL1-induced repression of MPF via the wee1 pathway. Other models describing an action of the clock on the cell cycle are for instance provided by Zámborszky et al 13 and Gérard and Goldbeter 14 , while studies of molecular interactions of cell cycle → clock coupling were made by Traynard et al 15 , Almeida et al 10 and Yan and Goldbeter 16 . Here, we propose yet a novel hypothesis: that of a clock that is responsive to Growth Factor (GF).…”

Section: Introductionmentioning

confidence: 99%

Cell cycle period control through modulation of clock inputs

Almeida

Chaves

Delaunay

2020

J. Bioinform. Comput. Biol.

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In this work, we study period control of the mammalian cell cycle via coupling with the cellular clock. For this, we make use of the oscillators’ synchronization dynamics and investigate methods of slowing down the cell cycle with the use of clock inputs. Clock control of the cell cycle is well established via identified molecular mechanisms, such as the CLOCK:BMAL1-mediated induction of the wee1 gene, resulting in the WEE1 kinase that represses the active form of mitosis promoting factor (MPF), the essential cell cycle component. To investigate the coupling dynamics of these systems, we use previously developed models of the clock and cell cycle oscillators and center our studies on unidirectional clock [Formula: see text] cell cycle coupling. Moreover, we propose an hypothesis of a Growth Factor (GF)-responsive clock, involving a pathway of the non-essential cell cycle complex cyclin D/CDK4. We observe a variety of rational ratios of clock to cell cycle period, such as: 1:1, 3:2, 4:3, and 5:4. Finally, our protocols of period control are successful in effectively slowing down the cell cycle by the use of clock modulating inputs, some of which correspond to existing drugs.

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Model-based investigation of the circadian clock and cell cycle coupling in mouse embryonic fibroblasts: Prediction of RevErb-α up-regulation during mitosis

Cited by 16 publications

References 34 publications

The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1

The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1

A Guided Tour of Artificial Intelligence Research

Cell cycle period control through modulation of clock inputs

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