Biology subjects

Oliver, S. G.

Publications and source records attributed to Oliver, S. G..

4 recordsLinked to original sources

bioRxiv2018

Saccharomyces cerevisiae adapted to grow in the presence of low-dose rapamycin exhibit altered amino acid metabolism

Rapamycin is a potent inhibitor of the highly conserved TOR kinase, the nutrient-sensitive controller of growth and aging. It has been utilised as a chemotherapeutic agent due to its anti-proliferative properties and as an immunosuppressive drug, and is also known to extend lifespan in a range of eukaryotes from yeast to mammals. However, the mechanisms through which eukaryotic cells adapt to sustained exposure to rapamycin have not yet been thoroughly investigated. Here, S. cerevisiae response to long-term rapamycin exposure was investigated by identifying the physiological, transcriptomic and metabolic differences observed for yeast populations inoculated into low-dose rapamycin-containing environment. The effect of oxygen availability and acidity of extracellular environment on this response was further deliberated by controlling or monitoring the dissolved oxygen level and pH of the culture. Yeast populations grown in the presence of rapamycin reached higher cell densities complemented by an increase in their chronological lifespan, and these physiological adaptations were associated with a rewiring of the amino acid metabolism, particularly that of arginine. The ability to synthesise amino acids emerges as the key factor leading to the major mechanistic differences between mammalian and microbial TOR signalling pathways in relation to nutrient recognition. Furthermore, oxygen levels and extracellular acidity of the culture were observed to conjointly affect yeast populations, virtually acting as coupled physiological effectors; cells were best adapted when maximal oxygenation of the culture was maintained in slightly acidic pH, any deviation necessitated more extensive readjustment to additional stress factors.

biochemistry↗

bioRxiv2017

Organisation of the transcriptional regulation of genes involved in protein transactions in yeast

The topological analyses of many large-scale molecular interaction networks often provide only limited insights into network function or evolution. In this paper, we argue that the functional heterogeneity of network components, rather than network size, is the main factor limiting the utility of topological analysis of large cellular networks. We have analysed large epistatic, functional, and transcriptional regulatory networks of genes that were attributed to the following biological process groupings: protein transactions, gene expression, cell cycle, and small molecule metabolism. Control analyses were performed on networks of randomly selected genes. We identified novel biological features emerging from the analysis of functionally homogenous biological networks irrespective of their size. In particular, direct regulation by transcription as an underrepresented feature of protein transactions. The analysis also demonstrated that the regulation of the genes involved in protein transactions at the transcriptional level was orchestrated by only a small number of regulators. Quantitative proteomic analysis of nuclear- and chromatin-enriched sub-cellular fractions of yeast provided supportive evidence for the conclusions generated by network analyses.

systems biology↗

bioRxiv2017

Estimating global enzyme abundance levels from cofactor requirements: a model-based analysis of the iron metabolism in yeast

Metabolic networks adapt to changes in their environment by modulating the activity of their enzymes and transporters; often by changing their abundance. Understanding such quantitative changes can shed light onto how metabolic adaptation works, or how it can fail and lead to a metabolically dysfunctional state. Unfortunately such data are only available on a fraction of the enzyme and transporter pools, and this leaves us distant from generating the full picture. We here propose a strategy to quantify metabolic protein requirements for cofactor-bearing enzymes and transporters through constraint-based modelling. In this work, we constructed the first eukaryotic genome-scale metabolic model with a comprehensive iron metabolism and investigated partial functional impairment of the genes involved in iron-sulphur (Fe-S) cluster maturation, which revealed extensive rewiring of the fluxes in silico, despite only marginal phenotypic dissimilarities. The yeast metabolism at steady state was determined to employ a constant iron-recruiting enzyme turnover at a rate of 3.02 x 10-11 mM / (g biomass)-1 h-1. Furthermore, we employed this model to identify and study a mutualistic relationship between Streptomyces coelicolor and Saccharomyces cerevisiae, which involves iron and folate sharing economies between the two microbes.

systems biology↗

bioRxiv2017

Heterogeneous chromatin mobility derived from chromatin states is a determinant of genome organisation in S. cerevisiae

Spatial organisation of the genome is essential for regulating gene activity, yet the mechanisms that shape this three-dimensional organisation in eukaryotes are far from understood. Here, we combine bioinformatic determination of chromatin states during normal growth and heat shock, and computational polymer modelling of genome structure, with quantitative microscopy and Hi-C to demonstrate that differential mobility of yeast chromosome segments leads to spatial self-organisation of the genome. We observe that more than forty percent of chromatin-associated proteins display a poised and heterogeneous distribution along the chromosome, creating a heteropolymer. This distribution changes upon heat shock in a concerted, state-specific manner. Simulating yeast chromosomes as heteropolymers, in which the mobility of each segment depends on its cumulative protein occupancy, results in functionally relevant structures, which match our experimental data. This thermodynamically driven self-organisation achieves spatial clustering of poised genes and mechanistically contributes to the directed relocalisation of active genes to the nuclear periphery upon heat shock.\n\nOne Sentence SummaryUnequal protein occupancy and chromosome segment mobility drive 3D organisation of the genome.

systems biology↗