Control strategies for the timing of intracellular events.

While the timing of intracellular events is essential for many cellular processes, gene expression inside a single cell can exhibit substantial cell-to-cell variability, raising the question of how cells ensure precision in event timing despite such stochasticity. We address this question by analyzing a biologically reasonable model of gene expression in the context of first passage time (FPT), focusing on two experimentally measurable statistics: mean FPT (MFPT) and timing variability (TV). We show that (1) transcriptional burst size (BS) and burst frequency (BF) can minimize the TV; (2) translational BS monotonically reduces the MFPT to a nonzero low bound; (3) the timescale of promoter kinetics can minimize both the MFPT and the TV, depending on the ratio of the on-switching rate over the off-switching rate; and (4) positive feedback regulation of any form can all minimize the TV, whereas negative feedback regulation of transcriptional BF or BS always enhances the TV. These control strategies can have broad implications for diverse cellular processes relying on precise temporal triggering of events.