Genes enriched in A/T-ending codons are co-regulated and conserved across mammals

Benisty, Hannah; Hernandez‐Alias, Xavier; Weber, Marc; Anglada-Girotto, Miquel; Mantica, Federica; Radusky, Leandro; Senger, Gökçe; Calvet, Ferriol; Weghorn, Donate; Irimia, Manuel; Schaefer, Martin H.; Serrano, Luis

doi:10.1016/j.cels.2023.02.002

Cited by 7 publications

(9 citation statements)

References 68 publications

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“…Attempts to elucidate tissue-specific codon optimality in mammalian tissues have been limited to date, and mostly relied on published datasets(Sun and Zhang, 2022) and public databases(Benisty et al, 2023), thus the analysis was usually limited by the data available. For example, no formal correlation between tRNA pools or tRNA modifications was made to explain codon optimality patterns or specific phenomena observed at the codon level in such published works(Benisty et al, 2023; Sun and Zhang, 2022), especially that the reliance on tRNA genes does not reflect actual tRNA transcript expression(Chan and Lowe, 2016). In addition, the reliance on codon adaptation index (CAI) or tRNA adaptation index (tAI) might also not be ideal in such contexts where tissue specific metrics are needed, given that these two metrics depend on genomic information and not actual mRNA or tRNA levels(Sabi et al, 2017; Sharp and Li, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…In their work, they found that the testis and brain are capable of expressing rare codons compared to other tissues. Attempts to elucidate tissue-specific codon optimality in mammalian tissues have been limited to date, and mostly relied on published datasets (Sun and Zhang, 2022) and public databases (Benisty et al, 2023), thus the analysis was usually limited by the data available. For example, no formal correlation between tRNA pools or tRNA modifications was made to explain codon optimality patterns or specific phenomena observed at the codon level in such published works (Benisty et al, 2023;Sun and Zhang, 2022), especially that the reliance on tRNA genes does not reflect actual tRNA transcript expression (Chan and Lowe, 2016).…”

Section: ⮚ Discussionmentioning

confidence: 99%

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tRNA modifications inform tissue specific mRNA translation and codon optimization

Ando,

Rashad,

Begley

et al. 2023

Preprint

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The tRNA epitranscriptome has been recognized as an important player in mRNA translation regulation. tRNA modifications, tRNA expression, and tRNA derived small RNAs (tsRNAs) all play important roles in physiology as well as in multiple pathologies. While the decoding capacity of tRNA is generally understood, there remains gaps in our knowledge of the role of various tRNA processes in fine-tuning translation at the codon level. Specifically, how tRNAs regulates codon usage and bias at the tissue or cell levels remain unexplored. Here, we analyzed seven tissues from mice for the expression of tRNA modifications, mature tRNAs, and tsRNAs. We combined our analysis with Ribo-seq and evaluated various metrics for codon usage and optimality between tissues. Our analysis revealed distinct enrichment patterns of tRNA modifications in tissues. For example, queuosine and mcm5U modifications were most enriched in the brain. In addition, we observed lower levels of tRNAs and tsRNAs in the spleen with higher levels of snRNAs and snoRNAs compared to other tissues. Using three different metrics for codon analysis; isoacceptors frequencies, total codon frequencies, and A-site pausing, we revealed a strong A/T vs G/C ending codons bias in most tissues. The brain was the least biased tissue and was unique compared to all other tissues on multiple levels. Finally, we observed a strong concordance between the expression of queuosine modifications and the optimality of their decoded codons. Our results reveal that tRNA modifications are master regulators of translation and codon usage and optimality across tissues.

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Section: Discussionmentioning

confidence: 99%

Section: ⮚ Discussionmentioning

confidence: 99%

tRNA modifications inform tissue specific mRNA translation and codon optimization

Ando,

Rashad,

Begley

et al. 2023

Preprint

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“…Specific tissue‐dependent or cell‐cycle dependent gene expression regulation patterns have been invoked to explain the codon usage‐limited gene expression for certain human genes, such as TLR7 or KRAS (Fu et al, 2018; Lampson et al, 2013; Newman et al, 2016). In the case of AT‐rich genes in vertebrates, such as PTBP2 , it has been suggested that enrichment In less‐used codons (i.e., A/T‐ending codons in the case of vertebrates) may be linked to conserved, coordinated expression regulation over phylogeny and across ontogeny (Benisty et al, 2023). The expression levels of the three PTBP paralogs are tissue‐dependent in humans (Figure S1) as well as through mammals (Figure S12) (Keppetipola et al, 2012; Spellman et al, 2007; Wagner & Garcia‐Blanco, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In the case of ATrich genes in vertebrates , such as PTBP2, it has been suggested that enrichment in less-used codons (i.e. A/T-ending codons in the case of vertebrates) may be linked to conserved, coordinated expression regulation over phylogeny and across ontogeny (Benisty et al, 2023). The expression levels of the three PTBP paralogs are tissue-dependent in humans (Supplementary Figure S1) as well as through mammals (Supplementary Figure S12) (Keppetipola et al, 2012;Wagner and Garcia-Blanco, 2002;Spellman et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…The poor-expression ability of PTBP2 in human cells, the increase in protein production by the introduction of common codons, along may be linked to conserved, coordinated expression regulation over phylogeny and across ontogeny (Benisty et al, 2023). The expression levels of the three PTBP paralogs are tissue-dependent in humans (Figure S1) as well as through mammals (Figure S12) (Keppetipola et al, 2012;Spellman et al, 2007;Wagner & Garcia-Blanco, 2002).…”

Section: F I G U R Ementioning

confidence: 99%

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Subfunctionalisation of paralogous genes and evolution of differential codon usage preferences: The showcase of polypyrimidine tract binding proteins

Bourret,

Borvető,

Bravo

2023

Journal of Evolutionary Biology

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Gene paralogs are copies of an ancestral gene that appear after gene or full genome duplication. When two sister gene copies are maintained in the genome, redundancy may release certain evolutionary pressures, allowing one of them to access novel functions. Here, we focused our study on gene paralogs on the evolutionary history of the three polypyrimidine tract binding protein genes (PTBP) and their concurrent evolution of differential codon usage preferences (CUPrefs) in vertebrate species. PTBP1‐3 show high identity at the amino acid level (up to 80%) but display strongly different nucleotide composition, divergent CUPrefs and, in humans and in many other vertebrates, distinct tissue‐specific expression levels. Our phylogenetic inference results show that the duplication events leading to the three extant PTBP1‐3 lineages predate the basal diversification within vertebrates, and genomic context analysis illustrates that local synteny has been well preserved over time for the three paralogs. We identify a distinct evolutionary pattern towards GC3‐enriching substitutions in PTBP1, concurrent with enrichment in frequently used codons and with a tissue‐wide expression. In contrast, PTBP2s are enriched in AT‐ending, rare codons, and display tissue‐restricted expression. As a result of this substitution trend, CUPrefs sharply differ between mammalian PTBP1s and the rest of PTBPs. Genomic context analysis suggests that GC3‐rich nucleotide composition in PTBP1s is driven by local substitution processes, while the evidence in this direction is thinner for PTBP2‐3. An actual lack of co‐variation between the observed GC composition of PTBP2‐3 and that of the surrounding non‐coding genomic environment would raise an interrogation on the origin of CUPrefs, warranting further research on a putative tissue‐specific translational selection. Finally, we communicate an intriguing trend for the use of the UUG‐Leu codon, which matches the trends of AT‐ending codons. Our results are compatible with a scenario in which a combination of directional mutation–selection processes would have differentially shaped CUPrefs of PTBPs in vertebrates: the observed GC‐enrichment of PTBP1 in placental mammals may be linked to genomic location and to the strong and broad tissue‐expression, while AT‐enrichment of PTBP2 and PTBP3 would be associated with rare CUPrefs and thus, possibly to specialized spatio‐temporal expression. Our interpretation is coherent with a gene subfunctionalisation process by differential expression regulation associated with the evolution of specific CUPrefs.

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Queuosine tRNA Modification: Connecting the Microbiome to the Translatome

Rashad

2024

BioEssays

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Transfer RNA (tRNA) modifications play an important role in regulating mRNA translation at the codon level. tRNA modifications can influence codon selection and optimality, thus shifting translation toward specific sets of mRNAs in a dynamic manner. Queuosine (Q) is a tRNA modification occurring at the wobble position. In eukaryotes, queuosine is synthesized by the tRNA‐guanine trans‐glycosylase (TGT) complex, which incorporates the nucleobase queuine (or Qbase) into guanine of the GUN anticodons. Queuine is sourced from gut bacteria and dietary intake. Q was recently shown to be critical for cellular responses to oxidative and mitochondrial stresses, as well as its potential role in neurodegenerative diseases and brain health. These unique features of Q provide an interesting insight into the regulation of mRNA translation by gut bacteria, and the potential health implications. In this review, Q biology is examined in the light of recent literature and nearly 4 decades of research. Q's role in neuropsychiatric diseases and cancer is highlighted and discussed. Given the recent interest in Q, and the new findings, more research is needed to fully comprehend its biological function and disease relevance, especially in neurobiology.

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Genes enriched in A/T-ending codons are co-regulated and conserved across mammals

Cited by 7 publications

References 68 publications

tRNA modifications inform tissue specific mRNA translation and codon optimization

tRNA modifications inform tissue specific mRNA translation and codon optimization

Subfunctionalisation of paralogous genes and evolution of differential codon usage preferences: The showcase of polypyrimidine tract binding proteins

Queuosine tRNA Modification: Connecting the Microbiome to the Translatome

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