Multiscale effects of heating and cooling on genes and gene networks

Significance Fluctuating environments such as changes in ambient temperature represent a fundamental challenge to life. Cells must protect gene networks that protect them from such stresses, making it difficult to understand how temperature affects gene network function in general. Here, we focus on single genes and small synthetic network modules to reveal four key effects of nonoptimal temperatures at different biological scales: (i) a cell fate choice between arrest and resistance, (ii) slower growth rates, (iii) Arrhenius reaction rates, and (iv) protein structure changes. We develop a multiscale computational modeling framework that captures and predicts all of these effects. These findings promote our understanding of how temperature affects living systems and enables more robust cellular engineering for real-world applications. Most organisms must cope with temperature changes. This involves genes and gene networks both as subjects and agents of cellular protection, creating difficulties in understanding. Here, we study how heating and cooling affect expression of single genes and synthetic gene circuits in Saccharomyces cerevisiae. We discovered that nonoptimal temperatures induce a cell fate choice between stress resistance and growth arrest. This creates dramatic gene expression bimodality in isogenic cell populations, as arrest abolishes gene expression. Multiscale models incorporating population dynamics, temperature-dependent growth rates, and Arrhenius scaling of reaction rates captured the effects of cooling, but not those of heating in resistant cells. Molecular-dynamics simulations revealed how heating alters the conformational dynamics of the TetR repressor, fully explaining the experimental observations. Overall, nonoptimal temperatures induce a cell fate decision and corrupt gene and gene network function in computationally predictable ways, which may aid future applications of engineered microbes in nonstandard temperatures.