Extrinsic Noise and Low-Level Pulsing Orchestrate

Bet-Hedging Responses

Javier Garcia-Bernardo1*, Mary J. Dunlop2

1 Department of Computer Science, University of Vermont, 301 Votey Hall, Burlington, VT 05405

2 School of Engineering, University of Vermont, 301 Votey Hall, Burlington, VT 05405

* Corresponding author: jgarciab@uvm.edu

ABSTRACT

Cells live in changing, uncertain environments, exposed to sudden increases in the concentration of stressors. In order to survive, cells cannot depend solely on sensory responses, which have a delay associated with them, instead they need to anticipate future changes. However, the continuous synthesis and maintenance of general stress response mechanisms has a high energy cost for the cell. To resolve this, cells can rely on phenotypic diversity, where only a few cells carry the burden of expressing resistance mechanisms, effectively bet-hedging against the sudden appearance of a stressor. Phenotypic diversity can be produced by fluctuations in gene expression and is observed in many stress response mechanisms. In this study, we show another role of noise in gene expression. By simulating a transcription factor that activates several downstream genes (single-input module) we discovered that even when the concentration of the regulator is kept at low levels, infrequent activation of the downstream genes is observed. Expression of the downstream genes can be coordinated in the presence of extrinsic noise or low-level upstream dynamics. We compared an activator with fixed expression to an activator with pulsing dynamics. With one downstream gene, there is little or no difference observed between the two activator profiles. However, when several downstream genes are studied together, the pulsing activator is able to coordinate the response, while maintaining the same cost for the cell. Furthermore, this cost can be tuned by modifying the frequency, duration and amplitude of the pulses of the activator, providing the cell with a flexible mechanism for tuning the dynamics. A similar effect is seen when all the downstream genes are subject to extrinsic noise in their expression. This coordination may not be exclusive to stress response mechanisms and has the potential to provide an advantage in all single-input modules where coordination and low levels of the regulator is desired.