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

• Published in: PLoS computational biology Vol. 15; no. 4; p. e1007017
• Main Authors: Sun, Qiwen, Jiao, Feng, Lin, Genghong, Yu, Jianshe, Tang, Moxun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2019; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Applied mathematics; B cells; Bacteria; Biology and Life Sciences; Burst size; Cell cycle; Cell Cycle - genetics; Cell Cycle - physiology; Cell division; Cell Line; Computational Biology; Computer simulation; Deoxyribonucleic acid; DNA; Dosage; Embryonic stem cells; Gene dosage; Gene duplication; Gene expression; Genes; Genetic aspects; Homeostasis; Kinetics; Medicine and Health Sciences; Messenger RNA; Mice; Models, Biological; Multiplication & division; Noise; Nonlinear Dynamics; Nonlinear systems; Numerical analysis; Protein expression; Proteins; Random variables; RNA; RNA polymerase; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stem cells; Transcription; Transcription (Genetics); Transcription, Genetic - genetics; Transcription, Genetic - physiology; Variation; Yeast; East Lansing Michigan; United States > US; China; Michigan
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1007017

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 stage [Formula: see text] and a late stage [Formula: see text]. 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 from [Formula: see text] to [Formula: see text] measured 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 in [Formula: see text], 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.