Starting too soon: upstream reading frames repress downstream translation

Abstract

Upstream open reading frames (uORFs) are known to regulate a few specific transcripts, and recent computational and experimental studies have suggested candidate uORF regulation across the genome. In this issue, Johnstone et al (2016) use ribosome profiling to identify translated uORFs and measure their effects on downstream translation. Furthermore, they show that regulatory uORFs are conserved across species and subject to selective constraint. Recognizing the potential of uORFs in regulating translation expands our understanding of the dynamic regulation of gene expression.

Figure 1. Ribosome profiling detects uORF translation and downstream repression

A) Ribosome profiling maps the location of ribosomes across a transcript using deep sequencing of ribosome protected fragments (RPFs) (Ingolia et al, 2009). In addition to the major protein coding sequence (CDS), RPFs can be seen in upstream open reading frames (uORF). B) RPFs offer nucleotide level resolution that can map to any of the three potential reading frames. Bazzini et al (2014) utilized this triplet periodicity to generate an ORFscore. This ORFscore can be used to classify actively translated regions. In this issue, Johnstone et al (2016) apply ORFscore classification to separate computationally defined uORFs by their translation status. C) Johnstone et al (2016) find that confidently translated uORFs correlate with repression of the downstream CDS translation. Moreover, overlapping open reading frames (oORFs) act as stronger repressors of CDS translation.