Cheng Jun, Maier Kerstin C, Avsec Žiga, Rus Petra, Gagneur Julien
Department of Informatics, Technical University of Munich, 85748 Garching, Germany.
Graduate School of Quantitative Biosciences (QBM), Ludwig-Maximilians-Universität München, 81377 München, Germany.
RNA. 2017 Nov;23(11):1648-1659. doi: 10.1261/rna.062224.117. Epub 2017 Aug 11.
The stability of mRNA is one of the major determinants of gene expression. Although a wealth of sequence elements regulating mRNA stability has been described, their quantitative contributions to half-life are unknown. Here, we built a quantitative model for based on functional mRNA sequence features that explains 59% of the half-life variation between genes and predicts half-life at a median relative error of 30%. The model revealed a new destabilizing 3' UTR motif, ATATTC, which we functionally validated. Codon usage proves to be the major determinant of mRNA stability. Nonetheless, single-nucleotide variations have the largest effect when occurring on 3' UTR motifs or upstream AUGs. Analyzing mRNA half-life data of 34 knockout strains showed that the effect of codon usage not only requires functional decapping and deadenylation, but also the 5'-to-3' exonuclease Xrn1, the nonsense-mediated decay genes, but not no-go decay. Altogether, this study quantitatively delineates the contributions of mRNA sequence features on stability in yeast, reveals their functional dependencies on degradation pathways, and allows accurate prediction of half-life from mRNA sequence.
mRNA的稳定性是基因表达的主要决定因素之一。尽管已经描述了大量调节mRNA稳定性的序列元件，但它们对半衰期的定量贡献尚不清楚。在此，我们基于功能性mRNA序列特征构建了一个定量模型，该模型解释了基因间59%的半衰期差异，并以30%的中位相对误差预测半衰期。该模型揭示了一个新的不稳定3'UTR基序ATATTC，我们对其进行了功能验证。密码子使用被证明是mRNA稳定性的主要决定因素。尽管如此，单核苷酸变异发生在3'UTR基序或上游AUG上时影响最大。分析34个基因敲除菌株的mRNA半衰期数据表明，密码子使用的影响不仅需要功能性的去帽和腺苷酸化，还需要5'到3'外切核酸酶Xrn1、无义介导的衰变基因，但不需要无义衰变。总之，这项研究定量地描述了mRNA序列特征对酵母中稳定性的贡献，揭示了它们对降解途径的功能依赖性，并允许从mRNA序列准确预测半衰期。
