TY - JOUR T1 - Sequence features explain most of the mRNA stability variation across genes in yeast JF - bioRxiv DO - 10.1101/085522 SP - 085522 AU - Jun Cheng AU - Žiga Avsec AU - Julien Gagneur Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/01/19/085522.abstract N2 - The stability of messenger RNA (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 Saccharomyces cerevisiae explaining 60% of the half-life variation between genes based on mRNA sequence features alone, and predicts half-life at a median relative error of 30%. The model integrates known cis-regulatory elements, identifies novel ones, and quantifies their contributions at single-nucleotide resolution. We show quantitatively that codon usage is the major determinant of mRNA stability. Nonetheless, single-nucleotide variations have the largest effect when occurring on 3’UTR motifs or upstream AUGs. Application of the approach to Schizosaccharomyces pombe supports the generality of these findings. Analyzing the effect of these sequence elements on 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 non-sense mediated decay proteins Upf2 and Upf3, and does not require 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.Author Summary The stability of mRNA plays a key role in gene regulation: It influences not only the mRNA abundance but also how quickly new steady-state levels are reached upon a transcriptional trigger. How is mRNA half-life encoded in a gene sequence? Through systematic discovery of novel half-life associated sequence elements and collecting known ones, we show that mRNA half-life can be predicted from sequence in yeast, at an accuracy close to measurement precision. Our analysis reveals new conserved motifs in 3’UTRs predictive for half-life. While codon usage appears to be the major determinant of half-life, motifs in 3’UTRs are the most sensitive elements to mutations: a single nucleotide change can affect the half-life of an mRNA by as much as 30%. Analyzing half-life data of knockout strains, we furthermore dissected the dependency of the elements with respect to various mRNA degradation pathways. This revealed the dependency of codon-mediated mRNA stability control to 5’-3’ degradation and non-sense mediated decay genes. Altogether, our study is a significant step forward in predicting gene expression from a genome sequence and understanding codon-mediated mRNA stability control. ER -