Department of Applied Science and Technology, Politecnico di Torino, Torino, Italy.
Italian Institute for Genomic Medicine, Torino, Italy.
PLoS Comput Biol. 2018 Apr 17;14(4):e1006063. doi: 10.1371/journal.pcbi.1006063. eCollection 2018 Apr.
Several studies highlighted the relevance of extrinsic noise in shaping cell decision making and differentiation in molecular networks. Bimodal distributions of gene expression levels provide experimental evidence of phenotypic differentiation, where the modes of the distribution often correspond to different physiological states of the system. We theoretically address the presence of bimodal phenotypes in the context of microRNA (miRNA)-mediated regulation. MiRNAs are small noncoding RNA molecules that downregulate the expression of their target mRNAs. The nature of this interaction is titrative and induces a threshold effect: below a given target transcription rate almost no mRNAs are free and available for translation. We investigate the effect of extrinsic noise on the system by introducing a fluctuating miRNA-transcription rate. We find that the presence of extrinsic noise favours the presence of bimodal target distributions which can be observed for a wider range of parameters compared to the case with intrinsic noise only and for lower miRNA-target interaction strength. Our results suggest that combining threshold-inducing interactions with extrinsic noise provides a simple and robust mechanism for obtaining bimodal populations without requiring fine tuning. Furthermore, we characterise the protein distribution's dependence on protein half-life.
几项研究强调了外在噪声在塑造分子网络中细胞决策和分化方面的相关性。基因表达水平的双峰分布为表型分化提供了实验证据，其中分布的模式通常对应于系统的不同生理状态。我们从理论上研究了 miRNA（microRNA）介导调控中双峰表型的存在。miRNA 是一种小的非编码 RNA 分子，可下调其靶 mRNA 的表达。这种相互作用的性质是滴定的，并诱导一个阈值效应：低于给定的靶转录率，几乎没有 mRNA 是自由的，可用于翻译。我们通过引入波动的 miRNA 转录率来研究外在噪声对系统的影响。我们发现，外在噪声的存在有利于双峰靶分布的存在，与仅存在内在噪声的情况相比，双峰靶分布的存在范围更广，而且与 miRNA-靶相互作用强度更低。我们的研究结果表明，将诱导阈值的相互作用与外在噪声相结合，提供了一种简单而稳健的机制，可在不需要微调的情况下获得双峰群体。此外，我们还描述了蛋白质分布对蛋白质半衰期的依赖性。
