Folding Free Energies of 5′-UTRs Impact Post-Transcriptional Regulation on a Genomic Scale in Yeast

Abstract

Using high-throughput technologies, abundances and other features of genes and proteins have been measured on a genome-wide scale in Saccharomyces cerevisiae. In contrast, secondary structure in 5′–untranslated regions (UTRs) of mRNA has only been investigated for a limited number of genes. Here, the aim is to study genome-wide regulatory effects of mRNA 5′-UTR folding free energies. We performed computations of secondary structures in 5′-UTRs and their folding free energies for all verified genes in S. cerevisiae. We found significant correlations between folding free energies of 5′-UTRs and various transcript features measured in genome-wide studies of yeast. In particular, mRNAs with weakly folded 5′-UTRs have higher translation rates, higher abundances of the corresponding proteins, longer half-lives, and higher numbers of transcripts, and are upregulated after heat shock. Furthermore, 5′-UTRs have significantly higher folding free energies than other genomic regions and randomized sequences. We also found a positive correlation between transcript half-life and ribosome occupancy that is more pronounced for short-lived transcripts, which supports a picture of competition between translation and degradation. Among the genes with strongly folded 5′-UTRs, there is a huge overrepresentation of uncharacterized open reading frames. Based on our analysis, we conclude that (i) there is a widespread bias for 5′-UTRs to be weakly folded, (ii) folding free energies of 5′-UTRs are correlated with mRNA translation and turnover on a genomic scale, and (iii) transcripts with strongly folded 5′-UTRs are often rare and hard to find experimentally. In cells, proteins are made from messenger RNA copied from genes in the DNA. The amount of each protein needs to be controlled by cells. For this purpose, cells use a strategy that includes decomposing RNA and varying the number of proteins made from each RNA. One part of the RNA molecule is called the 5′–untranslated region (UTR), and it is known that this region can fold into a three-dimensional structure. For some genes, such structures are important for protein production. In this article, structures in 5′-UTRs are calculated for all genes in the yeast Saccharomyces cerevisiae. The authors show that structures in 5′-UTRs likely play a role in RNA decomposition and protein production for many genes in the genome: RNA molecules with weakly folded 5′-UTRs live relatively longer and produce more proteins. This study provides an example of how genome-wide computational analysis complements experimental results.