Inference of the High-Level Interaction Topology between the Metabolic and Cell-Cycle Oscillators from Single-Cell Dynamics.

Recent evidence suggests that the eukaryotic metabolism is an autonomous oscillator. Together with oscillating elements of the cyclin/CDK machinery, this oscillator might form a coupled oscillator system, from which cell-cycle control emerges. The topology of interactions between the metabolic oscillator and the elements of the cyclin/CDK machinery, however, remains unknown.

goes through distinct metabolic phases during its replicative lifespan.

A comprehensive description of the phenotypic changes during cellular aging is key towards unraveling its causal forces. Previously, we mapped age-related changes in the proteome and transcriptome (Janssens et al., 2015).

An upper limit on Gibbs energy dissipation governs cellular metabolism.

The principles governing cellular metabolic operation are poorly understood. Because diverse organisms show similar metabolic flux patterns, we hypothesized that a fundamental thermodynamic constraint might shape cellular metabolism. Here, we develop a constraint-based model for Saccharomyces cerevisiae with a comprehensive description of biochemical thermodynamics including a Gibbs energy balance.

A guide to gene regulatory network inference for obtaining predictive solutions: Underlying assumptions and fundamental biological and data constraints.

The study of biological systems at a system level has become a reality due to the increasing powerful computational approaches able to handle increasingly larger datasets. Uncovering the dynamic nature of gene regulatory networks in order to attain a system level understanding and improve the predictive power of biological models is an important research field in systems biology. The task itself presents several challenges, since the problem is of combinatorial nature and highly depends on several biological constraints and also the intended application.

Autonomous Metabolic Oscillations Robustly Gate the Early and Late Cell Cycle.

Eukaryotic cell division is known to be controlled by the cyclin/cyclin dependent kinase (CDK) machinery. However, eukaryotes have evolved prior to CDKs, and cells can divide in the absence of major cyclin/CDK components. We hypothesized that an autonomous metabolic oscillator provides dynamic triggers for cell-cycle initiation and progression.

Temporal system-level organization of the switch from glycolytic to gluconeogenic operation in yeast.

The diauxic shift in Saccharomyces cerevisiae is an ideal model to study how eukaryotic cells readjust their metabolism from glycolytic to gluconeogenic operation. In this work, we generated time-resolved physiological data, quantitative metabolome (69 intracellular metabolites) and proteome (72 enzymes) profiles. We found that the diauxic shift is accomplished by three key events that are temporally organized: (i) a reduction in the glycolytic flux and the production of storage compounds before glucose depletion, mediated by downregulation of phosphofructokinase and pyruvate kinase reactions; (ii) upon glucose exhaustion, the reversion of carbon flow through glycolysis and onset of the glyoxylate cycle operation triggered by an increased expression of the enzymes that catalyze the malate synthase and cytosolic citrate synthase reactions; and (iii) in the later stages of the adaptation, the shutting down of the pentose phosphate pathway with a change in NADPH regeneration.

A flux-sensing mechanism could regulate the switch between respiration and fermentation.

The yeast Saccharomyces cerevisiae can show different metabolic phenotypes (e.g. fermentation and respiration).