First-passage time approach to controlling noise in the timing of intracellular events
Significance Understanding how randomness in the timing of intracellular events is buffered has important consequences for diverse cellular processes, where precision is required for proper functioning. To investigate event timing in noisy biochemical systems, we develop a first-passage time framework in which an event is triggered when a regulatory protein accumulates up to a critical level. Formulas quantifying event-timing fluctuations in stochastic models of protein synthesis with feedback regulation are developed. Formulas shed counterintuitive insights into regulatory mechanisms essential for scheduling an event at a precise time with minimal fluctuations. These results uncover various features in the biochemical pathways used by phages to lyse individually infected bacterial cells at an optimal time, despite stochastic expression of lysis proteins. In the noisy cellular environment, gene products are subject to inherent random fluctuations in copy numbers over time. How cells ensure precision in the timing of key intracellular events despite such stochasticity is an intriguing fundamental problem. We formulate event timing as a first-passage time problem, where an event is triggered when the level of a protein crosses a critical threshold for the first time. Analytical calculations are performed for the first-passage time distribution in stochastic models of gene expression. Derivation of these formulas motivates an interesting question: Is there an optimal feedback strategy to regulate the synthesis of a protein to ensure that an event will occur at a precise time, while minimizing deviations or noise about the mean? Counterintuitively, results show that for a stable long-lived protein, the optimal strategy is to express the protein at a constant rate without any feedback regulation, and any form of feedback (positive, negative, or any combination of them) will always amplify noise in event timing. In contrast, a positive feedback mechanism provides the highest precision in timing for an unstable protein. These theoretical results explain recent experimental observations of single-cell lysis times in bacteriophage [Formula]. Here, lysis of an infected bacterial cell is orchestrated by the expression and accumulation of a stable [Formula] protein up to a threshold, and precision in timing is achieved via feedforward rather than feedback control. Our results have broad implications for diverse cellular processes that rely on precise temporal triggering of events.
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