  Important cellular processes such as migration, differentiation, and
development 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
diminishing repressor. We find that the optimal strategy corresponds to a
nonlinear increase in the amount of the target molecule over time. 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, when we consider the effects of cell division, we find that
repression outperforms activation if division occurs late in the process. Our
results explain the nonlinear increase and low noise of mig-1 gene expression
in migrating neuroblast cells during Caenorhabditis 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 timing.
