Tian Shuangmei, Zhao Ziyu, Kassie Meharie G, Zhang Fangyuan, Ren Beibei, Wang Degeng
Department of Environmental Toxicology, and The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX 79416, USA.
Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX 79409-1042, USA.
bioRxiv. 2025 Feb 15:2025.02.11.637731. doi: 10.1101/2025.02.11.637731.
MicroRNA (miRNA) induced silencing complex (miRISC) is the targeting apparatus and arguably rate-limiting step of the miRNA-mediated regulatory subsystem - the major noise reducing though metabolically wasteful mechanism. Recently, we reported that miRISC channels miRNA-mediated regulatory activity back onto their own mRNAs to form negative self-feedback loops, a noise-reduction technique in engineering and synthetic/systems biology. Here, we describe mathematical modeling that predicts mRNA expression noise to correlate negatively with degradation rate ( ) and noise reduction by self-feedback control of . We also calculated and expression noise of mRNAs detected in a cutting-edge total-RNA single-cell RNA-seq (scRNA-seq) dataset. As predicted, miRNA-targeted mRNAs exhibited higher values in conjunction with lower inter-cell expression noise. Moreover, as predicted by our self-feedback loop model, miRISC mRNAs (AGO1/2/3 and TNRC6A/B/C) exhibited further reduced expression noise. In short, mathematical-modeling and total-RNA scRNA-seq data-analysis shed insight into operational trade-off between noise reduction and metabolic/energetic expenditure in producing miRNA-targeted mRNAs destined for enhanced degradation and translational inhibition, as well as negative self-feedback loop reinforcement of miRISC - the core of miRNA-mediated noise-reduction subsystem. To our knowledge, this is the first report of concurrent mRNA degradation and expression noise analyses and of noise reduction by self-feedback control of mRNA degradation.
微小RNA（miRNA）诱导沉默复合体（miRISC）是miRNA介导的调节子系统的靶向装置，也可以说是限速步骤，该调节子系统是主要的降噪机制，尽管代谢成本高昂。最近，我们报道miRISC将miRNA介导的调节活性反馈到其自身的mRNA上，形成负向自反馈环，这是工程学和合成/系统生物学中的一种降噪技术。在此，我们描述了数学模型，该模型预测mRNA表达噪声与降解速率（ ）呈负相关，且通过对 的自反馈控制实现降噪。我们还计算了在前沿的全RNA单细胞RNA测序（scRNA-seq）数据集中检测到的mRNA的 和表达噪声。正如预测的那样，miRNA靶向的mRNA表现出较高的 值，同时细胞间表达噪声较低。此外，正如我们的自反馈环模型所预测的，miRISC的mRNA（AGO1/2/3和TNRC6A/B/C）表现出进一步降低的表达噪声。简而言之，数学建模和全RNA scRNA-seq数据分析揭示了在产生旨在增强降解和翻译抑制的miRNA靶向mRNA过程中，降噪与代谢/能量消耗之间的操作权衡，以及miRISC的负向自反馈环强化，miRISC是miRNA介导的降噪子系统的核心。据我们所知,这是首次同时进行mRNA降解和表达噪声分析以及通过对mRNA降解的自反馈控制实现降噪的报道。
