Abstract
Heat is one of the most fundamental and ancient environmental stresses, and response mechanisms are found in prokaryotes and shared among most eukaryotes. In the budding yeast Saccharomyces cerevisiae, the heat stress response involves coordinated changes at all biological levels, from gene expression to protein and metabolite abundances, and to temporary adjustments in physiology. Due to its integrative multi-level-multi-scale nature, heat adaptation constitutes a complex dynamic process, which has forced most experimental and modeling analyses in the past to focus on just one or a few of its aspects. Here we review the basic components of the heat stress response in yeast and outline what has been done, and what needs to be done, to merge the available information into computational structures that permit comprehensive diagnostics, interrogation, and interpretation. We illustrate the process in particular with the coordination of two metabolic responses, namely the dramatic accumulation of the protective disaccharide trehalose and the substantial change in the profile of sphingolipids, which in turn affect gene expression. The proposed methods primarily use differential equations in the canonical modeling framework of Biochemical Systems Theory (BST), which permits the relatively easy construction of coarse, initial models even in systems that are incompletely characterized.
Highlights
In most cells, a strong temperature increase in the environmental milieu causes a stress response.Much is known about the details of this type of response (e.g., [1]) and yet, we do not have a comprehensive picture of how the response is organized, regulated and coordinated
Proteins respond to heat with three distinct changes of great importance: Temperature affects their production from mRNAs; their dynamics of degradation or deactivation; and their folding state, which often translates into changes in activity
Castells-Roca et al [7] published a genome-wide dataset containing mRNA amounts, as well as transcription and decay rates of each mRNA, obtained in a growing culture of yeast cells that were heat stressed by a temperature shift from 25 °C to 37 °C; the data were presented for several time points up to 40 min
Summary
A strong temperature increase in the environmental milieu causes a stress response. It is well understood that heat shock proteins are involved, genes up-regulated, signaling mechanisms triggered and metabolic profiles dramatically altered. Some of these changes commence within minutes and some may last for hours after the first exposure to heat. The question arises of how a cell manages to coordinate this complex, multi-level-multi-scale response Answering this question is quite challenging, due to the large number and heterogeneity of the involved molecules and the different time scales at which transcription, translation, metabolism, signal transduction, protein turnover, and other physiological processes occur. A difficult challenge is the appropriate selection of mathematical representations for the governing processes within the system In this project, we focus primarily on the metabolic level of the heat stress response in Saccharomyces cerevisiae. The pertinent set of contributors, while being too large for purely intuitive argumentation, is manageable with computational means
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