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Expression of many genes varies as a cell transitions through differentcell-cycle stages. How coupling between stochastic expression and cell cycleimpacts cell-to-cell variability (noise) in the level of protein is not wellunderstood. We analyze a model, where a stable protein is synthesized in randombursts, and the frequency with which bursts occur varies within the cell cycle.Formulas quantifying the extent of fluctuations in the protein copy number arederived and decomposed into components arising from the cell cycle andstochastic processes. The latter stochastic component represents contributionsfrom bursty expression and errors incurred during partitioning of moleculesbetween daughter cells. These formulas reveal an interesting trade-off:cell-cycle dependencies that amplify the noise contribution from burstyexpression also attenuate the contribution from partitioning errors. Weinvestigate existence of optimum strategies for coupling expression to the cellcycle that minimize the stochastic component. Intriguingly, results show that azero production rate throughout the cell cycle, with expression only occurringjust before cell division minimizes noise from bursty expression for a fixedmean protein level. In contrast, the optimal strategy in the case ofpartitioning errors is to make the protein just after cell division. We provideexamples of regulatory proteins that are expressed only towards the end of cellcycle, and argue that such strategies enhance robustness of cell-cycledecisions to the intrinsic stochasticity of gene expression.

Cell-cycle coupled expression minimizes random fluctuations in gene product levels