Mathematical modelling of the Yeast Metabolic Cycle

Thesis

The Yeast Metabolic Cycle (YMC) is an ultradian rhythm whose precise regulatory mechanism remains elusive. The YMC is a unique system that combines respiratory bursts with oscillations in both transcript levels and hundreds of metabolites in a tightly-controlled manner, creating an effective single-cell behavior that can be studied using sequencing techniques that require large quantities of cells. In this DPhil thesis I present a quantitative mathematical model of the YMC that is able to both describe the yeast synchronized metabolic activity and predict the outcome of several validating experiments.

Histone Modifications (HMs) are intimately related to gene activation and epigenetic changes regulated through chromatin organization. mRNA degradation is related to some HMs accumulation levels, and both are actively involved in the YMC regulatory mechanism. By comparing the RNA and HMs dynamics across the YMC, I have explored the functions of some HMs like H3K4me3 or H3 early-tail lysine acetylations in the yeast metabolism, discovering that H3K18ac abundance is incompatible with mRNA stability.

By clustering the yeast genome according to its expression dynamics during the YMC, I have revealed new insights into the way metabolic processes are compartmentalized at the different phases of the cycle and elucidated potential transcription factors like Met4p, Adr1p, or Thi2p, that may act as regulators of the different clusters, constituting a first attempt of unveiling the YMC regulatory mechanism.

I have employed these clusters as the cornerstone of a mathematical model describing RNA and protein dynamics at an isolated yeast cell using ordinary differential equations, concluding that a transcriptional oscillator guiding the yeast activity is more plausible that a fully metabolic oscillator.

Finally, I have combined a collection of three-component, robust, transcriptional oscillators entrained by a mean-field Hamiltonian to explain the coordination mechanisms underlying the origin and maintenance of the YMC. The resulting mathematical model is able to both replicate the YMC features described by the literature and predict the system behaviour when experimental conditions are changed or perturbations are introduced. In particular, our model explains the shape of the dissolved oxygen trace observed in the chemostat, replicates the spontaneous yeast synchronization obtained after a glucose starvation phase, and predicts the effect that carbon-source perturbations will have on the YMC.

Authors: Merchante González, A

• DOI: 10.5287/ora-orqx6bz4j
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Ultradian Rhythms; Yeast Metabolism; Computational Biochemistry; Data Analysis; Bioinformatics
• Subjects: Biochemistry