Benchmark for quantitative characterization of circadian clock cycles.

Understanding circadian clock mechanisms is fundamental in order to counteract the harmful effects of clock malfunctioning and associated diseases. Biochemical, genetic and systems biology approaches have provided invaluable information on the mechanisms of the circadian clock, from which many mathematical models have been developed to understand the dynamics and quantitative properties of the circadian oscillator. To better analyze and compare quantitatively all these circadian cycles, we propose a method based on a previously proposed circadian cycle segmentation into stages.

[Harmonic oscillations of circadian rhythms come out of the shadows].

About 40 % of the liver transcriptome display a circadian expression. Recently, harmonic oscillations of the circadian rhythm and independent of the circadian clock have been identified. Transcripts oscillating with a 12h period are involved in fundamental and ubiquitous cellular mechanisms such as proteostasis, lipid metabolism or RNA metabolism.

Cycle dynamics and synchronization in a coupled network of peripheral circadian clocks.

The intercellular interactions between peripheral circadian clocks, located in tissues and organs other than the suprachiasmatic nuclei of the hypothalamus, are still very poorly understood. We propose a theoretical and computational study of the coupling between two or more clocks, using a calibrated, reduced model of the circadian clock to describe some synchronization properties between peripheral cellular clocks. Based on a piecewise linearization of the dynamics of the mutual CLOCK:BMAL1/PER:CRY inactivation term, we suggest a segmentation of the circadian cycle into six stages, to help analyse different types of synchronization between two clocks, including single stage duration, total period and maximal amplitudes.

KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism.

The mammalian circadian timing system and metabolism are highly interconnected, and disruption of this coupling is associated with negative health outcomes. Krüppel-like factors (KLFs) are transcription factors that govern metabolic homeostasis in various organs. Many KLFs show a circadian expression in the liver.

A detailed map of coupled circadian clock and cell cycle with qualitative dynamics validation.

Background: The temporal coordination of biological processes by the circadian clock is an important mechanism, and its disruption has negative health outcomes, including cancer. Experimental and theoretical evidence suggests that the oscillators driving the circadian clock and the cell cycle are coupled through phase locking.

Results: We present a detailed and documented map of known mechanisms related to the regulation of the circadian clock, and its coupling with an existing cell cycle map which includes main interactions of the mammalian cell cycle.

MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice.

A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD).

Transcription-based circadian mechanism controls the duration of molecular clock states in response to signaling inputs.

The molecular oscillator of the mammalian circadian clock consists in a dynamical network of genes and proteins whose main regulatory mechanisms occur at the transcriptional level. From a dynamical point of view, the mechanisms leading to an oscillatory solution with an orderly protein peak expression and a clear day/night phase distinction remain unclear. Our goal is to identify the essential interactions needed to generate phase opposition between the activating CLOCK:BMAL1 and the repressing PER:CRY complexes and to better distinguish these two main clock molecular phases relating to rest/activity and fast/feeding cycles.

Mathematical modelling reveals unexpected inheritance and variability patterns of cell cycle parameters in mammalian cells.

The cell cycle is the fundamental process of cell populations, it is regulated by environmental cues and by intracellular checkpoints. Cell cycle variability in clonal cell population is caused by stochastic processes such as random partitioning of cellular components to progeny cells at division and random interactions among biomolecules in cells. One of the important biological questions is how the dynamics at the cell cycle scale, which is related to family dependencies between the cell and its descendants, affects cell population behavior in the long-run.

Maternal eating behavior is a major synchronizer of fetal and postnatal peripheral clocks in mice.

Most living organisms show circadian rhythms in physiology and behavior. These oscillations are generated by endogenous circadian clocks, present in virtually all cells where they control key biological processes. To study peripheral clocks in vivo, we developed an original model, the Rev-Luc mouse to follow noninvasively and longitudinally Rev-Luc oscillations in peripheral clocks using in vivo bioluminescence imaging.

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

Experimental observations have put in evidence autonomous self-sustained circadian oscillators in most mammalian cells, and proved the existence of molecular links between the circadian clock and the cell cycle. Some mathematical models have also been built to assess conditions of control of the cell cycle by the circadian clock. However, recent studies in individual NIH3T3 fibroblasts have shown an unexpected acceleration of the circadian clock together with the cell cycle when the culture medium is enriched with growth factors, and the absence of such acceleration in confluent cells.

Sexual Dimorphism in Circadian Physiology Is Altered in LXRα Deficient Mice.

The mammalian circadian timing system coordinates key molecular, cellular and physiological processes along the 24-h cycle. Accumulating evidence suggests that many clock-controlled processes display a sexual dimorphism. In mammals this is well exemplified by the difference between the male and female circadian patterns of glucocorticoid hormone secretion and clock gene expression.

A hybrid model of cell cycle in mammals.

Time plays an essential role in many biological systems, especially in cell cycle. Many models of biological systems rely on differential equations, but parameter identification is an obstacle to use differential frameworks. In this paper, we present a new hybrid modeling framework that extends René Thomas' discrete modeling.

The hepatic circadian clock regulates the choline kinase α gene through the BMAL1-REV-ERBα axis.

The circadian timing system adapts most of the mammalian physiology and behaviour to the 24 h light/dark cycle. This temporal coordination relies on endogenous circadian clocks present in virtually all tissues and organs and implicated in the regulation of key cellular processes including metabolism, transport and secretion. Environmental or genetic disruption of the circadian coordination causes metabolic imbalance leading for instance to fatty liver, dyslipidaemia and obesity, thereby contributing to the development of a metabolic syndrome state.

Coupling between the Circadian Clock and Cell Cycle Oscillators: Implication for Healthy Cells and Malignant Growth.

Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer.

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.

Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level.

Functional genomics identify Birc5/survivin as a candidate gene involved in the chronotoxicity of cyclin-dependent kinase inhibitors.

The circadian timing system orchestrates most of mammalian physiology and behavior in synchrony with the external light/dark cycle. This regulation is achieved through endogenous clocks present in virtually all body cells, where they control key cellular processes, including metabolism, transport, and the cell cycle. Consistently, it has been observed in preclinical cancer models that both the efficacy and toxicity of most chemotherapeutic drugs depend on their time of administration.

A circadian clock transcription model for the personalization of cancer chronotherapy.

Circadian timing of anticancer medications has improved treatment tolerability and efficacy several fold, yet with intersubject variability. Using three C57BL/6-based mouse strains of both sexes, we identified three chronotoxicity classes with distinct circadian toxicity patterns of irinotecan, a topoisomerase I inhibitor active against colorectal cancer. Liver and colon circadian 24-hour expression patterns of clock genes Rev-erbα and Bmal1 best discriminated these chronotoxicity classes, among 27 transcriptional 24-hour time series, according to sparse linear discriminant analysis.

Age-structured cell population model to study the influence of growth factors on cell cycle dynamics.

Cell proliferation is controlled by many complex regulatory networks. Our purpose is to analyse, through mathematical modeling, the effects of growth factors on the dynamics of the division cycle in cell populations. Our work is based on an age-structured PDE model of the cell division cycle within a population of cells in a common tissue.

The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism.

Mutations of clock genes can lead to diabetes and obesity. REV-ERBα, a nuclear receptor involved in the circadian clockwork, has been shown to control lipid metabolism. To gain insight into the role of REV-ERBα in energy homeostasis in vivo, we explored daily metabolism of carbohydrates and lipids in chow-fed, unfed, or high-fat-fed Rev-erbα(-/-) mice and their wild-type littermates.

Sex and dosing-time dependencies in irinotecan-induced circadian disruption.

Circadian disruption accelerates malignant growth; thus, it should be avoided in anticancer therapy. The circadian disruptive effects of irinotecan, a topoisomerase I inhibitor, was investigated according to dosing time and sex. In previous work, irinotecan achieved best tolerability following dosing at zeitgeber time (ZT) 11 in male and ZT15 in female mice, whereas worst toxicity corresponded to treatment at ZT23 and ZT3 in male and female mice, respectively.

Cancer inhibition through circadian reprogramming of tumor transcriptome with meal timing.

Circadian disruption accelerates cancer progression, whereas circadian reinforcement could halt it. Mice with P03 pancreatic adenocarcinoma (n = 77) were synchronized and fed ad libitum (AL) or with meal timing (MT) from Zeitgeber time (ZT) 2 to ZT6 with normal or fat diet. Tumor gene expression profiling was determined with DNA microarrays at endogenous circadian time (CT) 4 and CT16.

Kruppel-like factor KLF10 is a link between the circadian clock and metabolism in liver.

The circadian timing system coordinates many aspects of mammalian physiology and behavior in synchrony with the external light/dark cycle. These rhythms are driven by endogenous molecular clocks present in most body cells. Many clock outputs are transcriptional regulators, suggesting that clock genes primarily control physiology through indirect pathways.