Translation and Natural Selection of long non-canonical RNA micropeptides
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ABSTRACT:
PROVIDER: PRJNA842067 | ENA |
REPOSITORIES: ENA
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Project description:Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but lacking canonical coding sequences. Apparently unable to produce peptides, lncRNA function seems to only involve RNA sequence and structure. Here, we exhaustively detect in-vivo translation of small open reading frames (small ORFs) within lncRNAs using Ribosomal profiling during Drosophila melanogaster embryogenesis. We show that around 30% of lncRNAs contain small ORFs engaged by ribosomes, leading to regulated translation of 100 to 300 micropeptides. We identify lncRNA features that favour translation, such as cistronicity, Kozak sequences, and conservation. For this latter, we develop a bioinformatics pipeline to detect small ORF homologues, and we reveal evidence of natural selection favouring the conservation of micropeptide sequence and function across evolution. Our results expand the repertoire of lncRNA functions, and suggest that lncRNAs give rise to novel coding genes throughout evolution. Since most lncRNAs contain small ORFs with as yet unknown translation potential, we propose to rename them “long non-canonical RNAs”.
2022-11-02 | GSE204739 | GEO
Project description:A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future cancer genomics studies seeking to define new cancer targets.
| EGAS00001007426 | EGA
Project description:Despite being predicted to lack coding potential, cytoplasmic long non-coding (lnc)RNAs can associate with ribosomes. However, the landscape and biological relevance of 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 pervasively translated, which impacts their decay. We show that XUTs globally accumulate upon translation elongation inhibition, but not when initial ribosome loading is impaired. Ribo-Seq confirmed ribosomes binding to XUTs and identified ribosome-associated 5’-proximal small ORFs. Mechanistically, the NMD-sensitivity of XUTs mainly depends on the 3’-untranslated region length. Finally, we show that the peptide resulting from the translation of an NMD-sensitive XUT reporter exists in NMD-competent cells. Our work highlights the role of translation in the post-transcriptional metabolism of XUTs. We propose that XUT-derived peptides could be exposed to the natural selection, while NMD restricts XUTs levels.
2024-02-20 | GSE203283 | GEO
Project description:Tumor cells often exploit the protein translation machinery, resulting in enhanced protein expression essential for tumor growth. Since canonical translation initiation is often suppressed due to cell stress in the tumor microenvironment, non-canonical translation initiation mechanisms become particularly important for shaping the tumor proteome. EIF4G2 is a non-canonical translation initiation factor that mediates internal ribosome entry site (IRES) and upstream open reading frame (uORF) dependent initiation mechanisms, which can be used to modulate protein expression in cancer. Here we explored the contribution of EIF4G2 to cancer by screening the COSMIC database for EIF4G2 somatic mutations in cancer patients.
2023-08-21 | MSV000092704 | MassIVE
Project description:The Translation of Non-Canonical Open Reading Frames Controls Mucosal Immunity
| PRJNA494404 | ENA
Project description:Identification of non-canonical translation products in C. elegans using tandem mass spectrometry using available orbitrap data and experiments on timsTOF Pro
2021-07-29 | MSV000087909 | MassIVE
Project description:Translation initiation generally occurs at AUG codons in eukaryotes although it has been shown that non-AUG or non-canonical translation initiation can also occur. However, the evidence for non-canonical translation initiation sites (TISs) is largely indirect and based on ribosome profiling studies. Here, using a strategy specifically designed to enrich N-termini of proteins, we demonstrate that many human proteins are translated at non-canonical TISs. The large majority of TISs that mapped to 5’ untranslated regions were non-canonical and led to N-terminal extension of annotated proteins or translation of upstream small open reading frames (uORF). There has been little controversy on whether the corresponding amino acid to the start codon is incorporated at TIS or methionine is still incorporated. Notably, methionine was incorporated at almost all non-canonical TISs identified in this study. Comparison of the TISs determined through mass spectrometry with ribosome profiling data revealed that about two-thirds of the novel annotations were indeed supported by ribosome profiling data. The sequence orthology analysis and relative translation frequency analysis of non-canonical TISs over canonical ones suggests that those non-canonical TISs are not leaky but they can have certain biological functions. Overall, this study provides evidence of protein translation initiation at non-canonical TISs and indicates that further studies are required for elucidation of functional implications of such non-canonical translation initiation.
2017-11-23 | PXD006633 | Pride
Project description:This set of arrays contains all microarray experiments done involving comparisons among C. elegans natural isolates and mutation-accumulation lines. Abstract: The evolutionary importance of gene-expression divergence is unclear: some studies suggest that it is an important mechanism for evolution by natural selection, whereas others claim that most between-species regulatory changes are neutral or nearly neutral. We examined global transcriptional divergence patterns in a set of Caenorhabditis elegans mutation-accumulation lines and natural isolate lines to provide insights into the evolutionary importance of transcriptional variation and to discriminate between the forces of mutation and natural selection in shaping the evolution of gene expression. We detected the effects of selection on transcriptional divergence patterns and characterized them with respect to coexpressed gene sets, chromosomal clustering of expression changes and functional gene categories. We directly compared observed transcriptional variation patterns in the mutation-accumulation and natural isolate lines to a neutral model of transcriptome evolution to show that strong stabilizing selection dominates the evolution of transcriptional change for thousands of C. elegans expressed sequences. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Computed
2006-01-31 | E-GEOD-4123 | biostudies-arrayexpress
Project description:This set of arrays contains all microarray experiments done involving comparisons among C. elegans natural isolates and mutation-accumulation lines. Abstract: The evolutionary importance of gene-expression divergence is unclear: some studies suggest that it is an important mechanism for evolution by natural selection, whereas others claim that most between-species regulatory changes are neutral or nearly neutral. We examined global transcriptional divergence patterns in a set of Caenorhabditis elegans mutation-accumulation lines and natural isolate lines to provide insights into the evolutionary importance of transcriptional variation and to discriminate between the forces of mutation and natural selection in shaping the evolution of gene expression. We detected the effects of selection on transcriptional divergence patterns and characterized them with respect to coexpressed gene sets, chromosomal clustering of expression changes and functional gene categories. We directly compared observed transcriptional variation patterns in the mutation-accumulation and natural isolate lines to a neutral model of transcriptome evolution to show that strong stabilizing selection dominates the evolution of transcriptional change for thousands of C. elegans expressed sequences. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Keywords: all_pairs
2006-02-01 | GSE4123 | GEO
Project description:Translation is a fundamental step in gene expression that regulates multiple developmental and stress responses. One key step of translation is the association between eIF4E and eIF4G. This process is regulated in different eukaryotes by proteins which bind to eIF4E and block the formation of the eIF4E/eIF4G complex. Here, we report the discovery of CERES, the first functional eIF4E regulator described in plants. CERES is a modular protein that contains a LRR domain and a canonical eIF4E binding site (4E-BS), critical for CERES interaction with eIF4E in planta. CERES/eIF4E interaction excludes eIF4G from the complex. Despite this observation, CERES promotes translation in vivo interacts with eIF4A and with eIF3 in vivo and cosediments with translation initiation complexes in sucrose gradients. Moreover, ceres mutants display a sharp increase of the 80S peak and a reduction of polysome content at specific periods of the diel cycle. Super-resolution ribosome profiling demonstrates that these mutants show a change of translation efficiency of mRNAs related to light response and glucose management. Consistently, these mutants show a hypersensitive response to glucose. These data show that CERES is a “non canonical” translation initiation factor that, through the formation of alternative translation initiation complexes, modulates translation during the light cycle in plants.
2019-12-04 | GSE124290 | GEO