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EMBO J. 2016 Apr 1;35(7):706-23. doi: 10.15252/embj.201592759. Epub 2016 Feb 19.

Upstream ORFs are prevalent translational repressors in vertebrates.

Author information

1
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
2
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA antonio.giraldez@yale.edu.

Abstract

Regulation of gene expression is fundamental in establishing cellular diversity and a target of natural selection. Untranslated mRNA regions (UTRs) are key mediators of post-transcriptional regulation. Previous studies have predicted thousands of ORFs in 5'UTRs, the vast majority of which have unknown function. Here, we present a systematic analysis of the translation and function of upstream open reading frames (uORFs) across vertebrates. Using high-resolution ribosome footprinting, we find that (i)uORFs are prevalent within vertebrate transcriptomes, (ii) the majority show signatures of active translation, and (iii)uORFs act as potent regulators of translation and RNA levels, with a similar magnitude to miRNAs. Reporter experiments reveal clear repression of downstream translation by uORFs/oORFs. uORF number, intercistronic distance, overlap with the CDS, and initiation context most strongly influence translation. Evolution has targeted these features to favor uORFs amenable to regulation over constitutively repressive uORFs/oORFs. Finally, we observe that the regulatory potential of uORFs on individual genes is conserved across species. These results provide insight into the regulatory code within mRNA leader sequences and their capacity to modulate translation across vertebrates.

KEYWORDS:

gene regulation; ribosome profiling; translation; uORFs

PMID:
26896445
PMCID:
PMC4818764
[Available on 2017-04-01]
DOI:
10.15252/embj.201592759
[Indexed for MEDLINE]
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