Global analyses of UPF1 binding and function reveal expanded scope of nonsense-mediated mRNA decay
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Burge_Global analyses.pdf
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1.65 MB
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Author(s)
Hurt, Jessica A.
Robertson, Alex De Jong
Burge, Christopher B
Date Issued
June 2013
Journal
Genome Research
Publisher
Cold Spring Harbor Laboratory Press
Citation
Hurt, J. A., A. D. Robertson, and C. B. Burge. “Global analyses of UPF1 binding and function reveal expanded scope of nonsense-mediated mRNA decay.” Genome Research 23, no. 10 (October 1, 2013): 1636-1650. © 2013, Cold Spring Harbor Laboratory Press.
Version
Final published version
Abstract
UPF1 is a DNA/RNA helicase with essential roles in nonsense-mediated mRNA decay (NMD) and embryonic development. How UPF1 regulates target abundance and the relationship between NMD and embryogenesis are not well understood. To explore how NMD shapes the embryonic transcriptome, we integrated genome-wide analyses of UPF1 binding locations, NMD-regulated gene expression, and translation in murine embryonic stem cells (mESCs). We identified over 200 direct UPF1 binding targets using crosslinking/immunoprecipitation-sequencing (CLIP-seq) and revealed a repression pathway that involves 3′ UTR binding by UPF1 and translation but is independent of canonical targeting features involving 3′ UTR length and stop codon placement. Interestingly, NMD targeting of this set of mRNAs occurs in other mouse tissues and is conserved in human. We also show, using ribosome footprint profiling, that actively translated upstream open reading frames (uORFs) are enriched in transcription factor mRNAs and predict mRNA repression by NMD, while poorly translated mRNAs escape repression. Together, our results identify novel NMD determinants and targets and provide context for understanding the impact of UPF1 and NMD on the mESC transcriptome.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-Noncommercial 3.0
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DOI of Published Version
https://doi.org/10.1101/gr.157354.113
