Sturrock Marc, Li Shiyu, Shahrezaei Vahid
Department of Physiology, Royal College of Surgeons in Ireland, Dublin, Ireland.
Department of Mathematics, Imperial College London, London, United Kingdom.
J Theor Biol. 2017 Jul 7;424:55-72. doi: 10.1016/j.jtbi.2017.05.003. Epub 2017 May 5.
Gene expression is an inherently noisy process. This noise is generally thought to be deleterious as precise internal regulation of biochemical reactions is essential for cell growth and survival. Self-repression of gene expression, which is the simplest form of a negative feedback loop, is commonly believed to be employed by cellular systems to decrease the stochastic fluctuations in gene expression. When there is some delay in autoregulation, it is also believed that this system can generate oscillations. In eukaryotic cells, mRNAs that are synthesised in the nucleus must be exported to the cytoplasm to function in protein synthesis, whereas proteins must be transported into the nucleus from the cytoplasm to regulate the expression levels of genes. Nuclear transport thus plays a critical role in eukaryotic gene expression and regulation. Some recent studies have suggested that nuclear retention of mRNAs can control noise in mRNA expression. However, the effect of nuclear transport on protein noise and its interplay with negative feedback regulation is not completely understood. In this paper, we systematically compare four different simple models of gene expression. By using simulations and applying the linear noise approximation to the corresponding chemical master equations, we investigate the influence of nuclear import and export on noise in gene expression in a negative autoregulatory feedback loop. We first present results consistent with the literature, i.e., that negative feedback can effectively buffer the variability in protein levels, and nuclear retention can decrease mRNA noise levels. Interestingly we find that when negative feedback is combined with nuclear retention, an amplification in gene expression noise can be observed and is dependant on nuclear translocation rates. Finally, we investigate the effect of nuclear compartmentalisation on the ability of self-repressing genes to exhibit stochastic oscillatory dynamics.
基因表达是一个内在的噪声过程。一般认为这种噪声是有害的，因为生化反应的精确内部调节对于细胞生长和存活至关重要。基因表达的自我抑制是负反馈回路的最简单形式，通常认为细胞系统会利用它来减少基因表达中的随机波动。当自动调节存在一定延迟时，也认为该系统可以产生振荡。在真核细胞中，在细胞核中合成的mRNA必须输出到细胞质中才能在蛋白质合成中发挥作用，而蛋白质必须从细胞质转运到细胞核中以调节基因的表达水平。因此，核转运在真核基因表达和调控中起着关键作用。最近的一些研究表明，mRNA的核滞留可以控制mRNA表达中的噪声。然而，核转运对蛋白质噪声的影响及其与负反馈调节的相互作用尚未完全了解。在本文中，我们系统地比较了四种不同的简单基因表达模型。通过使用模拟并将线性噪声近似应用于相应的化学主方程，我们研究了核输入和输出对负自调节反馈回路中基因表达噪声的影响。我们首先给出与文献一致的结果，即负反馈可以有效地缓冲蛋白质水平的变异性，并且核滞留可以降低mRNA噪声水平。有趣的是，我们发现当负反馈与核滞留相结合时，可以观察到基因表达噪声的放大，并且这取决于核转运速率。最后，我们研究了核区室化对自我抑制基因表现出随机振荡动力学能力的影响。
