Wang Qirun, Lin Jie
Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
iScience. 2024 Jul 18;27(8):110531. doi: 10.1016/j.isci.2024.110531. eCollection 2024 Aug 16.
Many experiments showed that eukaryotic cells maintain a constant mRNA concentration upon various perturbations by actively regulating mRNA production and degradation rates, known as mRNA buffering. However, the underlying mechanism is still unknown. In this work, we unveil a mechanistic model of mRNA buffering: the releasing-shuttling (RS) model. The model incorporates two crucial proteins, X and Y, which play several roles, including transcription, decay, and export factors, in the different stages of mRNA metabolism. The RS model predicts the constant mRNA concentration under genome-wide genetic perturbations and cell volume changes, the slowed-down mRNA degradation after Pol II depletion, and the temporal transcription dynamics after exonuclease depletion, in agreement with multiple experiments. Finally, we present a list of X and Y candidates and propose an experimental method to identify X. Our work uncovers potentially universal pathways coupling transcription, export, and degradation that help cells maintain mRNA homeostasis.
许多实验表明，真核细胞通过积极调节mRNA的产生和降解速率，在各种扰动下维持恒定的mRNA浓度，这被称为mRNA缓冲。然而，其潜在机制仍然未知。在这项工作中，我们揭示了一种mRNA缓冲的机制模型：释放-穿梭（RS）模型。该模型纳入了两种关键蛋白X和Y，它们在mRNA代谢的不同阶段发挥多种作用，包括转录、衰变和输出因子。RS模型预测了在全基因组遗传扰动和细胞体积变化下的恒定mRNA浓度、RNA聚合酶II耗竭后mRNA降解的减缓以及核酸外切酶耗竭后的瞬时转录动态，这与多项实验结果一致。最后，我们列出了X和Y的候选蛋白，并提出了一种鉴定X的实验方法。我们的工作揭示了潜在的普遍途径，这些途径将转录、输出和降解联系起来，帮助细胞维持mRNA稳态。
