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Translational profiling of B cells infected with the Epstein-Barr virus reveals 5’ leader ribosome recruitment through upstream open reading frames

ABSTRACT: The Epstein-Barr virus (EBV) genome encodes several hundred transcripts. Using total RNA sequencing and ribosome profiling, we have characterized the transcriptional and translational scope of B cells infected with EBV. We could show that viral transcripts are translated at variable efficiency and that several viral genes show ribosome recruitment to the 5’ leader region of mRNAs. We used two different virus strains with differing in vitro characteristics to study EBV translation and could show that in cells infected with the weakly replicating EBV strain some lytic genes showed evidence of monosomal ribosome recruitment mainly in the 5’ leader region and on start codons in the absence of protein production. Finally, we could identify 25 novel upstream open reading frames that potentially regulate the translation efficiency of some viral genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81802 | GEO | 2017/12/29

SECONDARY ACCESSION(S): PRJNA322561

REPOSITORIES: GEO

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Translation initiation of the MgtL leader peptide is essential for the expression of mgtA in Escherichia coli

Project description:Riboswitches are cis-acting regulating RNA elements mostly found in the 5’-UTR of bacterial mRNAs. The Salmonella enterica mgtA riboswitch controls mgtA expression upon the sensing of intracellular Mg2+ ions. A leader peptide (MgtL) is contained within the mgtA riboswitch and its translation has been previously shown to be affected by Mg2+ concentrations. The current regulatory model suggests that the efficiency of MgtL translation is inversely related to mgtA transcription. Herein we show that the orthologue mgtA riboswitch of Escherichia coli also contains a leader peptide but, unlike S. enterica, that its translation is proportionally related to mgtA expression. Our results also suggest that ribosome stalling at mgtL is crucial for mgtA expression. Together, our results indicate that in E. coli, the expression of the MgtL leader peptide and mgtA are positively coordinated according to the intracellular Mg2+ concentration, a unique mechanism among known riboswitches.

2023-05-01 | GSE203590 | GEO

Gcn2 eIF2a kinase mediates combinatorial translational regulation through nucleotide motifs and uORFs in the mRNA 5’ leader regions

Project description:Cellular signaling controls translation through cis regulatory elements found in mRNAs. Gcn2 is the master regulator of translation during nutrient limitation in normal and cancer cells. Activated Gcn2 phosphorylates eIF2a, thereby repressing general translation while activating translation of specific mRNAs with upstream ORFs (uORFs) in its leader regions. Here we performed genome-wide measurement of mRNA translation during histidine starvation in fission yeast Schizosaccharomyces pombe. Polysomal microarray hybridization experiments identified a group of 1779 genes whose translation is up-regulated in Gcn2-dependent manner. We find that translation is reprogrammed to enhance organellar synthesis and transcription and repress ribosome synthesis. The 1779 genes included gcn5 and hri2 shown to promote growth under histidine starvation. They encode histone acetyl transferase and heme-binding eIF2a kinase activated by oxidative stress, and their 5’-leader contains 3 or 4 uORFs, respectively. Our reporter studies show that uORFs in gcn5 and hri2 operate similarly to those found in S. cerevisiae GCN4, the founding case for uORF-dependent regulation. Moreover, motif analysis identified 5’-UGA(C/G)GG-3’ as a motif promoting translation during starvation. Using hrd1 5’UTR with such a motif, we demonstrated its requirement in Gcn2-dependent translational control. To our knowledge, this is the first nucleotide motif found to be responsible for translational control by Gcn2. We propose that Gcn2 mediates translational control of more specific mRNAs than previously anticipated

2020-09-23 | GSE143299 | GEO

RNA G-quadruplexes mark repressive upstream open reading frames in human mRNAs

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.

2018-04-30 | GSE105082 | GEO

Induction of an alternative 5' leader enhances translation of Inpp5e and resistance to oncolytic virus infection

Project description:Residual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. Control of mRNA translation is an important feature of innate immunity, yet the identity of mRNA substrates that participate in host defences remain ill-defined. We characterized the translatome of resistant murine “4T1” breast cancer cells infected with three of the most clinically advanced oncolytic viruses: Herpes Simplex virus 1, Reovirus and Vaccinia virus. Common among all three infections were translationally de-repressed mRNAs including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signalling. We found that viral infection induced expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5’ leader and is efficiently translated. Furthermore, we show that INPP5E contributes to antiviral immunity by altering virus attachment. These findings uncover a role for translational control through alternative 5’ leader expression and assign an antiviral function to the ciliopathy gene INPP5E.

2019-11-30 | GSE137757 | GEO

Polysome profiling RNAseq of cells transfected with an oligonucleotide targeting the ES6S region of the 40S subunit

Project description:Polysome profiling experiments were carried out to identify the mRNAs that have altered the translation efficiency (counts in polysomal fraction/counts in monosomal fractions) in the presence of an oligonucleotide targeting a specific region of the ribosomal RNA, to study the implication of this region in the translation of specific mRNAs

2019-12-10 | GSE129651 | GEO

A Cdh3 - b-Catenin - Laminin signaling axis by a subset of breast tumor leader cells controls leader cell polarization and directional collective migration

Project description:Carcinoma dissemination can occur when heterogeneous tumor and tumor stromal cells clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and interact with the microenvironment to direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system that mimics native breast tumor microenvironment, we developed 3D computational models which hypothesize that leader cells generate high protrusive forces and overcome extracellular matrix (ECM) resistance. Using single cell sequencing, we reveal leader cells are heterogeneous, and we identify and isolate a unique Cadherin-3 (Cdh3) positive leader cell subpopulation necessary and sufficient to lead migration. Cdh3 controls leader cell protrusion dynamics and local production of Laminin-332 which is required for integrin/focal adhesion function. Our findings highlight how a subset of leader cells interact with the microenvironment to direct collective migration.

2022-11-25 | GSE171203 | GEO

Evolution of Translation Regulation in budding Yeast

Project description:Comparison of translation efficiency in S. cerevisiae, S. paradoxus, and their F1 hybrid. SRA submission number SRP028552; BioProject number PRJNA213844; Ribosome profiling was used to compare mRNA abundance, ribosome occupancy, and translation efficiency in two yeast species and their F1 hybrid.

2013-12-04 | E-GEOD-52119 | biostudies-arrayexpress

Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames

Project description:Mammalian gene expression displays widespread circadian oscillations. Rhythmic transcription underlies the core clock mechanism, but it cannot explain numerous observations made at the level of protein rhythmicity. We have used ribosome profiling in mouse liver to measure the translation of mRNAs into protein around-the-clock and at high temporal and nucleotide resolution. Transcriptome-wide, we discovered extensive rhythms in ribosome occupancy, and identified a core set of ≈150 mRNAs subject to particularly robust daily changes in translation efficiency. Cycling proteins produced from non-oscillating transcripts revealed thus far unknown rhythmic regulation associated with specific pathways (notably in iron metabolism, through the rhythmic translation of transcripts containing iron responsive elements), and indicated feedback to the rhythmic transcriptome through novel rhythmic transcription factors. Moreover, estimates of relative levels of core clock protein biosynthesis that we deduced from the data explained known features of the circadian clock better than did mRNA expression alone. Finally, we identified uORF translation as a novel regulatory mechanism within the clock circuitry. Consistent with the occurrence of translated uORFs in several core clock transcripts, loss-of-function of Denr, a known regulator of re-initiation after uORF usage and of ribosome recycling, led to circadian period shortening in cells. In summary, our data offer a framework for understanding the dynamics of translational regulation, circadian gene expression, and metabolic control in a solid mammalian organ.

2015-10-14 | GSE67305 | GEO

Transcript leader elements contribute to competitive discrimination of mRNAs by the translational machinery

Project description:Pools of yeast transcript leaders display differential ribosome recruitment in yeast lysates.

2018-12-01 | GSE98788 | GEO

Advancing Trypanosoma brucei genome annotation through ribosome profiling and spliced leader mapping

Project description:Since the initial publication of the trypanosomatid genomes, curation has been ongoing. Here we apply the technique of ribosome profiling to Trypanosoma brucei, identifying 223 new coding regions by virtue of ribosome occupancy in the corresponding transcripts. A small number of these putative genes correspond to extra copies of previously annotated genes but 85% are novel. The median size of these novels CDSs is small (74 aa) indicating that past annotation work has excelled at detecting large CDSs. Of the unique CDSs discovered here, over half have candidate orthologues in other trypanosomatid genomes, most of which were not yet annotated as genes. Still, approximately one-third of the new CDSs were found only in T. brucei subspecies. When combined with RNA-seq and spliced leader mapping, we were able to definitively revise the start sites for 430 CDSs as compared to the current gene models. Such data also allowed us to use a structured approach to eliminate 701 putative genes as protein-coding. Finally, the data pointed to several regions of the genome that had sequence errors that altered coding region boundaries. Ribosome profiling and mRNA libraries were constructed in triplicate from in vitro PCF and in vivo BF lifestages of theT. brucei Treu927 and in vitro T. brucei Lister427, to evaluate role of translational gene regulation

2015-12-22 | E-GEOD-72463 | biostudies-arrayexpress

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