Cytoplasmic long noncoding RNAs are differentially regulated and translated during human neuronal differentiation

Douka, Katerina; Birds, Isabel; Wang, Dapeng; Kosteletos, Andreas; Clayton, Sophie; Byford, Abigail; Vasconcelos, Elton J R; O’Connell, Mary J.; Deuchars, Jim; Whitehouse, Adrian; Aspden, Julie L.

doi:10.1261/rna.078782.121

Cited by 26 publications

(26 citation statements)

References 89 publications

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“…However, accumulating experimental evidence lead us to re-evaluate this assumption. In fact, lncRNAs co-purify with polysomes in different models, including yeast (Smith et al ., 2014) and human cells (Carlevaro-Fita et al ., 2016; Douka et al, 2021; van Heesch et al ., 2014). In addition, high-throughput sequencing of ribosome-bound fragments using Ribo-Seq or related approaches has uncovered smORFs within lncRNAs (Aspden et al ., 2014; Chen et al ., 2020; Douka et al ., 2021; Ingolia et al ., 2014; Ingolia et al ., 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, lncRNAs co-purify with polysomes in different models, including yeast (Smith et al ., 2014) and human cells (Carlevaro-Fita et al ., 2016; Douka et al, 2021; van Heesch et al ., 2014). In addition, high-throughput sequencing of ribosome-bound fragments using Ribo-Seq or related approaches has uncovered smORFs within lncRNAs (Aspden et al ., 2014; Chen et al ., 2020; Douka et al ., 2021; Ingolia et al ., 2014; Ingolia et al ., 2011). Finally, several studies reported the identification of peptides resulting from the translation of smORFs carried on lncRNAs (Chen et al ., 2020; D’Lima et al ., 2017; Douka et al ., 2021; Matsumoto et al ., 2017; Slavoff et al ., 2013; Zanet et al ., 2015).…”

Section: Discussionmentioning

confidence: 99%

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Translation is a key determinant controlling the fate of cytoplasmic long non-coding RNAs

Andjus

Szachnowski

Vogt

et al. 2022

Preprint

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SummaryDespite predicted to lack coding potential, cytoplasmic long non-coding (lnc)RNAs can associate with ribosomes, resulting in some cases into the production of functional peptides. However, the biological and mechanistic relevance of this pervasive lncRNAs translation remains poorly studied. In yeast, cytoplasmic Xrn1-sensitive lncRNAs (XUTs) are targeted by the Nonsense-Mediated mRNA Decay (NMD), suggesting a translation-dependent degradation process. Here, we report that XUTs are translated, which impacts their abundance. We show that XUTs globally accumulate upon translation elongation inhibition, but not when initial ribosome loading is impaired. Translation also affects XUTs independently of NMD, by interfering with their decapping. Ribo-Seq confirmed ribosomes binding to XUTs and identified actively translated small ORFs in their 5’-proximal region. Mechanistic analyses revealed that their NMD-sensitivity depends on the 3’-untranslated region length. Finally, we detected the peptide derived from the translation of an NMD-sensitive XUT reporter in NMD-competent cells. Our work highlights the role of translation in the metabolism of XUTs, which could contribute to expose genetic novelty to the natural selection, while NMD restricts their expression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Translation is a key determinant controlling the fate of cytoplasmic long non-coding RNAs

Andjus

Szachnowski

Vogt

et al. 2022

Preprint

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“…Total nucleic acid was extracted from input samples using TRIzol™ LS (Invitrogen™), as described by the manufacturer. Sucrose fractions containing 80S and polysome ribosomes were used for poly-ribo-seq as previously described 58,59 . Fractions for each sample were pooled and diluted (100 mM Tris/HCl (pH 7.6), 30 mM NaCl and 10 mM MgCl 2 ) to a 10% sucrose concentration and ribosomes footprinted with 1 U/1×10 6 cells RNase I (Thermo Fisher), rotating overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs

Murphy

Schumann

Harrington

et al. 2022

Preprint

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Historically, ribosomes have been viewed as unchanged homogeneous macromolecular machines with no intrinsic regulatory capacity for mRNA translation. However, an emerging concept is that heterogeneity of ribosomal composition exists, which can exert a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct specialised ribosomes that actively regulate mRNA translation. Viruses lack their own translational machinery and impose a high translational demand on the host cell during replication. Here we explore the possibility that Kaposi sarcoma associated herpesvirus can manipulate host ribosome biogenesis during infection to produce specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis has identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic KSHV replication. Intriguingly, we demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and a previously uncharacterised KSHV lytic protein, ORF11, with small ribosomal subunit precursor complexes during lytic KSHV infection. Notably, BUD23 depletion resulted in significantly reduced viral gene expression and progression through the lytic cascade, culminating in a dramatic reduction of infectious virion production. Importantly, ribosome profiling demonstrated that BUD23 is essential for the reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the main open reading frame. Together our results provide new mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes to facilitate efficient translation of viral mRNAs.

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“…We used MTLN as an example of genuine protein coding RNA and illustrated typical features of ribosome profiling data and codon substitution patterns associated with genuine ORF translation and protein coding evolution. Expression of lncRNAs is highly specific (Hon et al, 2017;Douka et al, 2021), therefore a long RNA isoform of MTLN (ENST00000414416) may be expressed in some cells, however, translation of such mRNA is unlikely to produce MTLN proteoforms since its start codon cannot be reached by scanning preinitiation complex.…”

Section: Final Thoughtsmentioning

confidence: 99%

Exploring Evidence of Non-coding RNA Translation With Trips-Viz and GWIPS-Viz Browsers

Zaheed

Kiniry

Baranov

et al. 2021

Front. Cell Dev. Biol.

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Detection of translation in so-called non-coding RNA provides an opportunity for identification of novel bioactive peptides and microproteins. The main methods used for these purposes are ribosome profiling and mass spectrometry. A number of publicly available datasets already exist for a substantial number of different cell types grown under various conditions, and public data mining is an attractive strategy for identification of translation in non-coding RNAs. Since the analysis of publicly available data requires intensive data processing, several data resources have been created recently for exploring processed publicly available data, such as OpenProt, GWIPS-viz, and Trips-Viz. In this work we provide a detailed demonstration of how to use the latter two tools for exploring experimental evidence for translation of RNAs hitherto classified as non-coding. For this purpose, we use a set of transcripts with substantially different patterns of ribosome footprint distributions. We discuss how certain features of these patterns can be used as evidence for or against genuine translation. During our analysis we concluded that the MTLN mRNA, previously misannotated as lncRNA LINC000116, likely encodes only a short proteoform expressed from shorter RNA transcript variants.

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Cytoplasmic long noncoding RNAs are differentially regulated and translated during human neuronal differentiation

Cited by 26 publications

References 89 publications

Translation is a key determinant controlling the fate of cytoplasmic long non-coding RNAs

Translation is a key determinant controlling the fate of cytoplasmic long non-coding RNAs

Kaposi’s sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs

Exploring Evidence of Non-coding RNA Translation With Trips-Viz and GWIPS-Viz Browsers

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