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Gene transcription is a noisy process, and cell division cycle is an important source of gene transcription noise. In this work, we develop a mathematical approach by coupling transcription kinetics with cell division cycles to delineate how they are combined to regulate transcription output and noise. In view of gene dosage, a cell cycle is divided into an early stageS  1and a late stageS  2. The analytical forms for the mean and the noise of mRNA numbers are given in each stage. The analysis based on these formulas predicts precisely the fold change  r * of mRNA numbers fromS  1toS  2measured in a mouse embryonic stem cell line. When transcription follows similar kinetics in both stages,  r * buffers against DNA dosage variation and  r * ∈ (1, 2). Numerical simulations suggest that increasing cell cycle durations up-regulates transcription with less noise, whereas rapid stage transitions induce highly noisy transcription. A minimization of the transcription noise is observed when transcription homeostasis is attained by varying a single kinetic rate. When the transcription level scales with cellular volume, either by reducing the transcription burst frequency or by increasing the burst size inS  2, the noise shows only a minor variation over a wide range of cell cycle stage durations. The reduction level in the burst frequency is nearly a constant, whereas the increase in the burst size is conceivably sensitive, when responding to a large random variation of the cell cycle durations and the gene duplication time.

The nonlinear dynamics and fluctuations of mRNA levels in cell cycle coupled transcription