Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, the Netherlands; Oncode Institute, Nijmegen, the Netherlands.
Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, the Netherlands.
Cell Syst. 2024 Jun 19;15(6):526-543.e7. doi: 10.1016/j.cels.2024.05.004.
Poly(A) tails are crucial for mRNA translation and degradation, but the exact relationship between tail length and mRNA kinetics remains unclear. Here, we employ a small library of identical mRNAs that differ only in their poly(A)-tail length to examine their behavior in human embryonic kidney cells. We find that tail length strongly correlates with mRNA degradation rates but is decoupled from translation. Interestingly, an optimal tail length of ∼100 nt displays the highest translation rate, which is identical to the average endogenous tail length measured by nanopore sequencing. Furthermore, poly(A)-tail length variability-a feature of endogenous mRNAs-impacts translation efficiency but not mRNA degradation rates. Stochastic modeling combined with single-cell tracking reveals that poly(A) tails provide cells with an independent handle to tune gene expression fluctuations by decoupling mRNA degradation and translation. Together, this work contributes to the basic understanding of gene expression regulation and has potential applications in nucleic acid therapeutics.
聚（A）尾对于 mRNA 的翻译和降解至关重要，但尾长与 mRNA 动力学之间的确切关系仍不清楚。在这里，我们利用一小段仅在聚（A）尾长度上有所不同的相同 mRNA 来研究它们在人胚肾细胞中的行为。我们发现，尾长与 mRNA 降解率强烈相关，但与翻译无关。有趣的是，约 100 个核苷酸的最佳尾长显示出最高的翻译率，与通过纳米孔测序测量的平均内源性尾长相同。此外，聚（A）尾长的可变性——内源性 mRNAs 的一个特征——影响翻译效率，但不影响 mRNA 降解率。随机建模结合单细胞跟踪揭示，聚（A）尾为细胞提供了一个独立的控制手段，通过使 mRNA 降解和翻译解耦来调节基因表达的波动。总之，这项工作有助于对基因表达调控的基本理解，并在核酸治疗中有潜在的应用。
