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Copy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation [ATAC-seq]

ABSTRACT: The number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-Seq, RNA-seq and proteomics we observed distinct molecular consequences of individual tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoder genes buffer the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least six tRNA-Phe alleles is required for embryonic viability and tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA genes is required to buffer translation and viability in mammals.

ORGANISM(S): Mus musculus

PROVIDER: GSE200783 | GEO | 2023/03/05

REPOSITORIES: GEO

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Copy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation (RNA-seq)

Project description:The number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-Seq, RNA-seq and proteomics we observed distinct molecular consequences of individual tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoder genes buffer the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least six tRNA-Phe alleles is required for embryonic viability and tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA genes is required to buffer translation and viability in mammals.

2023-03-05 | GSE223662 | GEO

Copy number variation in tRNA isodecoders impairs mammalian development and balanced translation

Project description:The number of tRNA isodecoder genes has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-seq, RNA-seq and proteomics we observed distinct molecular consequences of individual tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoders compensate for the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least four tRNA-Phe isodecoders is required for embryonic development and survival. The loss of tRNA-Phe-1-1 and any other three tRNA-Phe genes causes embryonic lethality indicating that tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA isodecoder genes is required to buffer translation and viability in mammals.

2023-04-19 | PXD029684 | Pride

Transcriptome profile of S. cerevisiae strains expressing mistranslating tRNAs

Project description:Mistranslation, the mis-incorporation of an amino acid not specified by the “standard” genetic code, occurs in all cells. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. The goal of this study was to assess the transcriptome changes in yeast cells expressing two different mistranslating tRNA variants which mistranslate at similar frequencies (of ~ 3%) but result in different substitutions, namely alanine at proline codons or serine at arginine codons.

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Transcription profiling of yeast in response to mRNA mistranslation after 20 hours of induction

Project description:Transcriptome analysis in cells after 20 hours of mistranslation induction in relation to control cells at the same time point where mistranslation was not induced (without the inducible tRNA construction)

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Identification of proline to serine mistranslation in Drosophila melanogaster pupae

Project description:Transfer RNAs (tRNAs) are the adaptor molecules required for reading of the genetic code and the accurate production of proteins. tRNA variants can lead to genome-wide mistranslation, the misincorporation of amino acids not specified by the standard genetic code, into nascent proteins. While genome sequencing has identified putative mistranslating tRNA variants in human populations, little is known regarding how mistranslation affects multicellular organisms. Here, we create a Drosophila melanogaster model for mistranslation by integrating a serine tRNA variant that mistranslates serine for proline (tRNA(Ser)[UGG, G26A]) into the fly genome. Using mass spectrometry, we find that tRNA(Ser)[UGG, G26A] misincorporates serine for proline at a frequency of ~ 0.6% per codon. This model will enable studies into the synergistic effects of mistranslating tRNA variants and disease-causing alleles.

2021-09-18 | PXD028498 | Pride

Identification of tRNA sequences in Lactococcus lactis

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Evolution of robustness to protein mistranslation by accelerated protein turnover

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2015-11-06 | E-GEOD-65718 | biostudies-arrayexpress

Evolution of robustness to protein mistranslation by accelerated protein turnover

2015-11-06 | GSE65718 | GEO

Identifying the transcriptomic effects of tRNA-induced proline-to-serine mistranslation in Drosophila melanogaster

Project description:Mistranslation describes the misincorporation of an amino acid into a nascent polypeptide. Mistranslation has diverse effects on multicellular eukaryotes and is implicated in several human diseases. We introduced a mistranslating serine transfer RNA (tRNA) into Drosophila melanogaster that misincorporates serine at proline codons and found that it affected male and female flies differently. Here, we compare the transcriptomic response of male and female flies to mistranslation to identify cellular pathways that underlie this sex-specific response. Both males and females downregulated genes associated with metabolism in response to proline-to-serine mistranslation. Only males downregulated genes associated with developmental processes and response to negative stimuli such as infection, whereas only females downregulated aerobic respiration and ATP synthesis genes. Both sexes upregulated genes associated with gametogenesis but females upregulated cell cycle and DNA maintenance genes, suggesting that mistranslation may compromise genome integrity in females. This transcriptomic analysis advances our understanding of how males and females respond to mistranslation and has important implications for future studies that examine the influence of mistranslation on disease.

2024-05-11 | GSE256332 | GEO

Differential expression of human tRNA genes drives the abundance of tRNA-derived fragments

Project description:The human genome encodes hundreds of tRNA genes but their individual contribution to the tRNA pool is not fully understood. Deep sequencing of tRNA transcripts (tRNA-Seq) can estimate tRNA abundance at single gene resolution, but tRNA structures and post-transcriptional modifications impair these analyses. Here we present a bioinformatics strategy to investigate differential tRNA gene expression and use it to compare tRNA-Seq datasets from cultured human cells and human brain. We find that sequencing caveats affect quantitation of only a subset of human tRNA genes. Unexpectedly, we detect several cases where the differences in tRNA expression among samples do not involve variations at the level of isoacceptor tRNA sets (tRNAs charged with the same amino acid but using different anticodons); but rather among tRNA genes within the same isodecoder set (tRNAs having the same anticodon sequence). Because isodecoder tRNAs are functionally equal in terms of genetic translation, their differential expression may be related to non-canonical tRNA functions. We show that several instances of differential tRNA gene expression result in changes in the abundance of tRNA-derived fragments (tRFs) but not of mature tRNAs. Examples of differentially expressed tRFs include: PIWI-associated RNAs, tRFs present in tissue samples but not in cells cultured in vitro, and somatic tissue-specific tRFs. Our data support that differential expression of tRNA genes regulate non-canonical tRNA functions performed by tRFs.

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