Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

Abstract

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 Saccharomyces cerevisiae 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.

Decoupling the impact of microRNAs on translational repression versus RNA degradation in embryonic stem cells

“…For example, between the 25th and 75th percentile of mRNA stability, there was a 3.2-fold difference in stability and between the top and bottom 1% of mRNA stability there was over a 64-fold difference ( Figure 2A ). To identify features that explain the range of mRNA stabilities observed, we performed multiple linear regression taking into account the following features that previous studies implicated in affecting mRNA stability: 3’ UTR length, 5’ UTR length, CDS length, 3’ UTR GC content, 5’ UTR GC content, CDS GC content, AU-rich elements (ARE), miRNA-binding sites, number of exons in the transcript, and upstream ORFs ( Chan and Mugler, 2017 ; Cheng et al, 2017 ; Sharova et al, 2009 ). Combined, these features explained 25% of the variation in mRNA stability.…”

“…Mammalian mRNAs display a wide range of half-lives ranging from minutes to over a day ( Schwanhäusser et al, 2011 ). The wide range of mRNA stabilities are regulated by both intrinsic sequence features as well as the binding of regulatory factors such as microRNAs and RNA-binding proteins ( Cheng et al, 2017 ; Hasan et al, 2014 ; Wu and Brewer, 2012 ). However, the identity and how such features and regulatory factors impact mRNA stability are not well understood.…”

The Correlation Between DsRed mRNA Levels and Transient DsRed Protein Expression in Plants Depends on Leaf Age and the 5′ Untranslated Region

“…Interestingly, the CHS 5′UTR with the LPH leader peptide was associated with the highest DsRed mRNA levels for both promoters, and the decline in expression post‐infiltration was delayed (Figure B for 35SS and FigureJ for nos ). Differences in the GC‐content, coding sequence and 5′UTR length as well as folding energy of the mRNA may be responsible for this outcome . For example, the folding energy of the TL 5′UTR is about −180 kJ mol −1 compared to approximately −75 kJ mol −1 for the others .…”

mRNA Deadenylation Is Coupled to Translation Rates by the Differential Activities of Ccr4-Not Nucleases

“…Targeted deadenylation occurs when proteins bound to specific mRNA sequences recruit the Ccr4-Not complex ( Goldstrohm et al., 2006 , Stowell et al., 2016 , Wahle and Winkler, 2013 ). The action of these mRNA-binding proteins does not, however, fully account for the wide range of half-lives observed across the eukaryotic transcriptome ( Cheng et al., 2017 ). An additional major determinant of mRNA decay is the rate of translation elongation, and this correlates with codon optimality ( Presnyak et al., 2015 ).…”