Understanding global resource allocation in fission yeast through data analysis and coarse-grained mathematical modelling
File(s)
Author(s)
Kleijn, Istvan Tariq
Type
Thesis
Abstract
Unicellular organisms can grow in a large variety of environments. Even in those supporting robust growth, cellular resources are limited and their relative allocation to gene expression programmes determines physiological states and global properties such as the growth rate and the cell size. I have approached this topic from two angles, namely a comprehensive analysis of a gene expression data set and the construction of coarse-grained resource allocation models (C-GRAMs).
First, I studied a combined data set of protein and transcript abundances during growth of the fission yeast Schizosaccharomyces pombe on various abundant nitrogen sources. Approximately half of gene expression was significantly correlated with the growth rate, and this came alongside wide-spread nutrient-specific expression. Genes positively correlated with the growth rate participated in protein production, whereas those negatively correlated mainly belonged to the environmental stress response programme. Critically, the expression of metabolic enzymes was mainly condition specific.
Second, C-GRAMs are simple models of single cells, where large components of the macromolecular composition are abstracted into single entities. The dynamics and steady-state behaviour of such models can then be easily explored. A minimal C-GRAM with nitrogen and carbon pathways converging on biomass production described the effects of the uptake of sugars, ammonium, and/or compound nutrients such as amino acids on the translational resource allocation towards proteome sectors that maximised the growth rate. Prompted by new observations that the relation between cell volume and the growth rate was identical for both carbon and nitrogen perturbations, but that the surface-to-volume ratio was elevated in low-nitrogen conditions, I extended this to a C-GRAM that additionally accounted for the cell cycle, cell division, cell wall biosynthesis, and the effect of molecular crowding on the ribosomal efficiency.
First, I studied a combined data set of protein and transcript abundances during growth of the fission yeast Schizosaccharomyces pombe on various abundant nitrogen sources. Approximately half of gene expression was significantly correlated with the growth rate, and this came alongside wide-spread nutrient-specific expression. Genes positively correlated with the growth rate participated in protein production, whereas those negatively correlated mainly belonged to the environmental stress response programme. Critically, the expression of metabolic enzymes was mainly condition specific.
Second, C-GRAMs are simple models of single cells, where large components of the macromolecular composition are abstracted into single entities. The dynamics and steady-state behaviour of such models can then be easily explored. A minimal C-GRAM with nitrogen and carbon pathways converging on biomass production described the effects of the uptake of sugars, ammonium, and/or compound nutrients such as amino acids on the translational resource allocation towards proteome sectors that maximised the growth rate. Prompted by new observations that the relation between cell volume and the growth rate was identical for both carbon and nitrogen perturbations, but that the surface-to-volume ratio was elevated in low-nitrogen conditions, I extended this to a C-GRAM that additionally accounted for the cell cycle, cell division, cell wall biosynthesis, and the effect of molecular crowding on the ribosomal efficiency.
Version
Open Access
Date Issued
2022-04
Date Awarded
2022-06
Copyright Statement
Creative Commons Attribution Licence
License URL
Advisor
Shahrezaei, Vahid
Sponsor
Wellcome Trust (London, England)
Grant Number
203968/Z/16/Z
Publisher Department
Mathematics
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)