  Timing is essential for many cellular processes, from cellular responses to
external stimuli to the cell cycle and circadian clocks. Many of these
processes are based on gene expression. For example, an activated gene may be
required to reach in a precise time a threshold level of expression that
triggers a specific downstream process. However, gene expression is subject to
stochastic fluctuations, naturally inducing an uncertainty in this
threshold-crossing time with potential consequences on biological functions and
phenotypes. Here, we consider such "timing fluctuations", and we ask how they
can be controlled. Our analytical estimates and simulations show that, for an
induced gene, timing variability is minimal if the threshold level of
expression is approximately half of the steady-state level. Timing fuctuations
can be reduced by increasing the transcription rate, while they are insensitive
to the translation rate. In presence of self-regulatory strategies, we show
that self-repression reduces timing noise for threshold levels that have to be
reached quickly, while selfactivation is optimal at long times. These results
lay a framework for understanding stochasticity of endogenous systems such as
the cell cycle, as well as for the design of synthetic trigger circuits.
