Temporal precision of molecular events with regulation and feedback

TL;DR

This paper explores how specific regulatory strategies in molecular networks can optimize the timing precision of cellular events, revealing that combined feedback and regulation minimize timing noise.

Contribution

It develops a method to calculate optimal regulation functions that reduce timing noise and analyzes all two-node networks with regulation and feedback.

Findings

Feedback alone increases noise.

Regulation by a second species decreases noise.

Optimal regulation maximizes sequential events before threshold crossing.

Abstract

Cellular behaviors such as migration, division, and differentiation rely on precise timing, and yet the molecular events that govern these behaviors are highly stochastic. We investigate regulatory strategies that decrease the timing noise of molecular events. Autoregulatory feedback increases noise. Yet, we find that in the presence of regulation by a second species, autoregulatory feedback decreases noise. To explain this finding, we develop a method to calculate the optimal regulation function that minimizes the timing noise. The method reveals that the combination of feedback and regulation minimizes noise by maximizing the number of molecular events that must happen in sequence before a threshold is crossed. We compute the optimal timing precision for all two-node networks with regulation and feedback, derive a generic lower bound on timing noise, and discuss our results in the context of neuroblast migration during Caenorhabditis elegans development.