A coarse-grained resource allocation model of carbon and nitrogen metabolism in unicellular microbes

Coarse-grained resource allocation models (C-GRAMs) are simple mathematical models of cell physiology, where large components of the macromolecular composition are abstracted into single entities. The dynamics and steady-state behaviour of such models provides insights on optimal allocation of cellular resources and have explained experimentally observed cellular growth laws, but current models do not account for the uptake of compound sources of carbon and nitrogen. Here, we formulate a C-GRAM with nitrogen and carbon pathways converging on biomass production, with parametrizations accounting for respirofermentative and purely respiratory growth. The model describes 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 maximized the growth rate. It robustly recovers cellular growth laws including the Monod law and the ribosomal growth law. Furthermore, we show how the growth-maximizing balance between carbon uptake, recycling, and excretion depends on the nutrient environment. Lastly, we find a robust linear correlation between the ribosome fraction and the abundance of amino acid equivalents in the optimal cell, which supports the view that simple regulation of translational gene expression can enable cells to achieve an approximately optimal growth state

Growth-rate dependent and nutrient-specific gene expression resource allocation in fission yeast

Cellular resources are limited and their relative allocation to gene expression programmes determines physiological states and global properties such as the growth rate. Here, we determinedtheimportanceof the growth rate in explaining relative changes in protein and mRNA levels in the simple eukaryote Schizosaccharomyces pombegrownon non-limiting nitrogen sources. Although expression of half of fission yeast genes was significantly correlated with the growth rate, this came alongside wide-spread nutrient-specific regulation. Proteome and transcriptome often showed coordinated regulation but with notable exceptions, such as metabolic enzymes. Genes positively correlated with growth rate participated in every level of protein production apart fromRNA polymerase II-dependent transcription.Negatively correlated genes belonged mainly to the environmental stress response programme. Critically, metabolic enzymes, which represent ~55-70% of the proteome by mass,showedmostly condition-specificregulation.In summary, we provide a rich account of resource allocation to gene expression in a simple eukaryote, advancing our 19basic understanding of the interplay between growth-rate dependent and nutrient-specific gene expression

Growth-rate dependent and nutrient-specific gene expression resource allocation in fission yeast

Cellular resources are limited and their relative allocation to gene expression programmes determines physiological states and global properties such as the growth rate. Here, we determinedtheimportanceof the growth rate in explaining relative changes in protein and mRNA levels in the simple eukaryote Schizosaccharomyces pombegrownon non-limiting nitrogen sources. Although expression of half of fission yeast genes was significantly correlated with the growth rate, this came alongside wide-spread nutrient-specific regulation. Proteome and transcriptome often showed coordinated regulation but with notable exceptions, such as metabolic enzymes. Genes positively correlated with growth rate participated in every level of protein production apart fromRNA polymerase II-dependent transcription.Negatively correlated genes belonged mainly to the environmental stress response programme. Critically, metabolic enzymes, which represent ~55-70% of the proteome by mass,showedmostly condition-specificregulation.In summary, we provide a rich account of resource allocation to gene expression in a simple eukaryote, advancing our 19basic understanding of the interplay between growth-rate dependent and nutrient-specific gene expression

Predictive biology: modelling, understanding and harnessing microbial complexity

Predictive biology is the next great chapter in synthetic and systems biology, particularly for microorganisms. Tasks that once seemed infeasible are increasingly being realized such as designing and implementing intricate synthetic gene circuits that perform complex sensing and actuation functions, and assembling multi-species bacterial communities with specific, predefined compositions. These achievements have been made possible by the integration of diverse expertise across biology, physics and engineering, resulting in an emerging, quantitative understanding of biological design. As ever-expanding multi-omic data sets become available, their potential utility in transforming theory into practice remains firmly rooted in the underlying quantitative principles that govern biological systems. In this Review, we discuss key areas of predictive biology that are of growing interest to microbiology, the challenges associated with the innate complexity of microorganisms and the value of quantitative methods in making microbiology more predictable.Defence Threat Reduction Agency (Grant HDTRA1-15-1-0051