RNA G-quadruplexes mark repressive upstream open reading frames in human mRNAs
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ABSTRACT:
PROVIDER: PRJNA414611 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6181530.fastq.gz | Fastqsanger.gz | |||
| SRR6181540.fastq.gz | Fastqsanger.gz | |||
| SRR6181550.fastq.gz | Fastqsanger.gz | |||
| SRR6181560.fastq.gz | Fastqsanger.gz | |||
| SRR6181570.fastq.gz | Fastqsanger.gz |
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Project description:Translational control is a key determinant of protein abundance, which in turns defines the physiology and pathology of human cells. Initiation of translation is highly regulated in eukaryotes and is considered as the rate-limiting step of protein synthesis. mRNA secondary structures in 5’ untranslated region (UTR) and associated helicases have been characterised as key determinants of translation initiation. Nevertheless the transcriptome-wide contribution of non-canonical secondary structures, such as RNA G-quadruplexes (rG4s), to the translation of human mRNAs remains largely unappreciated. Here we use a ribosome profiling strategy to investigate the translational landscape associated to rG4s-containing mRNAs and the contribution of two rG4s-specialised DExH-box helicases, DHX9 and DHX36, to translation initiation in human cells. We show that rG4-forming sequences in 5’-UTR is associated with decreased translation efficiency which correlate with an increased ribosome density within the 5’-UTRs. We found that rG4s contribute to the translation of upstream open reading frames, and as a consequence, thwart the translation of the associated protein coding sequences (CDS). Depletion of the DHX36 and DHX9 helicases demonstrated that the formation of the rG4 structural motif rather than its nucleotide sequence mediate translation initiation. Our findings unveil a role for non-canonical structures in defining alternative 5’ starts for human mRNAs translation initiation.
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Project description:Translation of upstream open reading frames in a model of neuronal differentiation
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Project description:Upstream open reading frames (uORFs) initiate translation within mRNA 5’ leaders,and have the potential to altermain coding sequence(CDS) translationontranscripts in which they reside. Ribosome profiling(RP)studies suggest that translating ribosomes are pervasive within 5’ leadersacross model systems. However, the significance of this observationremains unclear. To explore a role for uORF usage in neuronal differentiation, we performed RP on undifferentiated and differentiated human neuroblastoma cells. Using a spectral coherence algorithm (SPECtre),we identify4,954uORFsacross31%of all neuroblastoma transcripts. These uORFspredominantly utilize non-AUG initiationcodonsand exhibit translational efficiencies(TE)comparable to annotated coding regions. Usage of both AUG initiated uORFs and aconservedandconsistently translated subset of non-AUG initiated uORFs correlateswith repressed CDS translation. Ribosomal protein transcripts are enriched in uORFs, and select uORFs on such transcripts were validated for expression. Withneuronal differentiation, we observedan overall positive correlation between translational shifts in uORF/CDSpairs. However,a subset of transcripts exhibit inverse shifts in translation of uORF/CDSpairs. TheseuORFsare enriched in AUG initiation sites, non-overlapping, and shorterin length. Cumulatively, CDSs downstream of uORFs characterized by persistent translation show smaller shifts in TE withneuronal differentiation relative to CDSs without a predicted uORF, suggesting that fluctuations in CDS translation are buffered by uORF translation. In sum, this work provides insights into the dynamic relationshipsand potential regulatory functionsof uORF/CDS pairs in a model of neuronal differentiation.
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Project description:The 5' untranslated region (UTR) sequence of eukaryotic mRNAs may contain upstream open reading frames (uORFs), which can regulate translation of the main open reading frame (mORF). The current model of translational regulation by uORFs posits that when a ribosome scans an mRNA and encounters a uORF, translation of that uORF can prevent ribosomes from reaching the mORF and cause decreased mORF translation. In this study, we first observed that rare variants in the 5' UTR dysregulate protein abundance. Upon further investigation, we found that rare variants near the start codon of uORFs can repress or derepress mORF translation, causing allelic changes in protein abundance. This finding holds for common variants as well, and common variants that modify uORF start codons also contribute disproportionately to metabolic and whole-plant phenotypes, suggesting that translational regulation by uORFs serves an adaptive function. These results provide evidence for the mechanisms by which natural sequence variation modulates gene expression, and ultimately, phenotype.
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