Temporal precision of regulated gene expression

Cellular processes such as cell migration, differentiation, and division often rely on precise timing. Yet, the molecular machinery that regulates timing is inherently noisy. How do cells achieve precise timing with noisy components? We investigate this question using a first-passage-time approach, for an event triggered by a molecule that crosses an abundance threshold and that is regulated by either an accumulating activator or a degrading repressor. We find that the optimal strategy corresponds to a nonlinear increase of the target molecule over time. The optimality arises from a tradeoff between minimizing the extrinsic timing noise of the regulator, and minimizing the intrinsic timing noise of the target molecule itself. Although either activation or repression outperforms an unregulated strategy, we find that repression outperforms activation in the presence of cell division that occurs late in the process. Our results explain the nonlinear increase and low noise of mig-1 gene expression in migrating neuroblast cells during C. elegans development, and suggest that mig-1 regulation is dominated by repression for maximal temporal precision. These findings suggest that dynamic regulation may be a simple and powerful strategy for precise cellular timekeeping.