Two microbiome metabolites compete for tRNA modification and mammalian cell proliferation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA978085 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR24785446_1.fastq.gz | Fastqsanger.gz | |||
| SRR24785446_2.fastq.gz | Fastqsanger.gz | |||
| SRR24785452_1.fastq.gz | Fastqsanger.gz | |||
| SRR24785452_2.fastq.gz | Fastqsanger.gz |
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Project description:Microbiome interacts with the eukaryotic host through many metabolites to affect cell physiology. A direct molecular pathway of microbial-host interaction is the incorporation of the microbial metabolite queuine at the wobble anticodon nucleotide of host tRNAs by a host enzyme that regulates host cell translation. Microbes also produce the intermediary metabolite pre-queuosine1 (preQ1) in the queuine pathway, and how preQ1 affects the host cell biology has not been explored. Here we show that preQ1 strongly represses human and mouse cell proliferation, but this effect is suppressed or reversible with queuine and depends on the same host enzyme that installs queuosine tRNA modification. PreQ1 and queuine are present in plasma and mouse tissues and incorporated into tRNA in cells and in mice, and preQ1 reduces mouse xenograft tumor growth. Mechanistically, preQ1 reduces cognate tRNA levels specifically and translation of house-keeping genes in a highly codon dependent manner. Genomic-wide CRISPR screen and validation identify pathways in sterol biosynthesis regulation, lipid metabolism, and Golgi-ER transport that mitigate the preQ1 proliferation effects through alleviation of cognate tRNA levels. Our results show an inter-dependent relationship of two microbial metabolites from the same biosynthesis pathway that compete and regulate host cell proliferation through multiple pathways.
2025-06-02 | GSE233846 | GEO
Project description:Queuosine (Q) is a conserved tRNA modification in the wobble anticodon position of tRNAs that read codons of Tyr/His/Asn/Asp. Eukaryotic tRNA Q-modification requires the metabolite queuine – derived from diet or catabolism of the gut microbiome – and a host-genome encoded enzyme complex, QTRT1/QTRT2. tRNA Q-modification has been shown to regulate translational efficiency, but the response of the mammalian transcriptome and tRNAome to tRNA Q-modification in the context of cell proliferation has not been thoroughly investigated. Using cells that differ only in their tRNA Q-modification levels, we found that both human HEK293T cultures and the primary, murine bone marrow-derived dendritic cells (BMDCs) proliferate faster when tRNA Q-modification level is high. We carried out tRNA-seq and mRNA-seq to elucidate the molecular mechanisms underlying this phenotype, revealing distinct tRNA modification and transcriptome changes associated with altered proliferation. In both cell types, the m22G26 tRNA modification is positively correlated to Q-modification, consistent with its reported role in enhancing translational efficiency. We also find that elevated Q-modification levels result in transcriptome changes, but in a context-dependent manner. In HEK293T cells, upregulated genes are in catabolic processes and signaling pathway activation; whereas in BMDCs, upregulated genes are in immune response mediation, proliferation, and immunoglobulin diversification. Codon usage analysis of differentially expressed transcripts is consistent with Q-modification enhancing the translation of ribosomal proteins, which increases cell proliferation. We also find that tRNA Q-modification increases surface presentation of MHC-II in BMDCs. Our results provide insights into the broader implications of tRNA Q-modifications in regulating diverse biological functions.
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Project description:Queuosine (Q) is a conserved tRNA modification in the wobble anticodon position of tRNAs that read codons of Tyr/His/Asn/Asp. Eukaryotic tRNA Q-modification requires the metabolite queuine – derived from diet or catabolism of the gut microbiome – and a host-genome encoded enzyme complex, QTRT1/QTRT2. tRNA Q-modification has been shown to regulate translational efficiency, but the response of the mammalian transcriptome and tRNAome to tRNA Q-modification in the context of cell proliferation has not been thoroughly investigated. Using cells that differ only in their tRNA Q-modification levels, we found that both human HEK293T cultures and the primary, murine bone marrow-derived dendritic cells (BMDCs) proliferate faster when tRNA Q-modification level is high. We carried out tRNA-seq and mRNA-seq to elucidate the molecular mechanisms underlying this phenotype, revealing distinct tRNA modification and transcriptome changes associated with altered proliferation. In both cell types, the m22G26 tRNA modification is positively correlated to Q-modification, consistent with its reported role in enhancing translational efficiency. We also find that elevated Q-modification levels result in transcriptome changes, but in a context-dependent manner. In HEK293T cells, upregulated genes are in catabolic processes and signaling pathway activation; whereas in BMDCs, upregulated genes are in immune response mediation, proliferation, and immunoglobulin diversification. Codon usage analysis of differentially expressed transcripts is consistent with Q-modification enhancing the translation of ribosomal proteins, which increases cell proliferation. We also find that tRNA Q-modification increases surface presentation of MHC-II in BMDCs. Our results provide insights into the broader implications of tRNA Q-modifications in regulating diverse biological functions.
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Project description:Queuosine (Q) is a conserved tRNA modification in the wobble anticodon position of tRNAs that read codons of Tyr/His/Asn/Asp. Eukaryotic tRNA Q-modification requires the metabolite queuine – derived from diet or catabolism of the gut microbiome – and a host-genome encoded enzyme complex, QTRT1/QTRT2. tRNA Q-modification has been shown to regulate translational efficiency, but the response of the mammalian transcriptome and tRNAome to tRNA Q-modification in the context of cell proliferation has not been thoroughly investigated. Using cells that differ only in their tRNA Q-modification levels, we found that both human HEK293T cultures and the primary, murine bone marrow-derived dendritic cells (BMDCs) proliferate faster when tRNA Q-modification level is high. We carried out tRNA-seq and mRNA-seq to elucidate the molecular mechanisms underlying this phenotype, revealing distinct tRNA modification and transcriptome changes associated with altered proliferation. In both cell types, the m22G26 tRNA modification is positively correlated to Q-modification, consistent with its reported role in enhancing translational efficiency. We also find that elevated Q-modification levels result in transcriptome changes, but in a context-dependent manner. In HEK293T cells, upregulated genes are in catabolic processes and signaling pathway activation; whereas in BMDCs, upregulated genes are in immune response mediation, proliferation, and immunoglobulin diversification. Codon usage analysis of differentially expressed transcripts is consistent with Q-modification enhancing the translation of ribosomal proteins, which increases cell proliferation. We also find that tRNA Q-modification increases surface presentation of MHC-II in BMDCs. Our results provide insights into the broader implications of tRNA Q-modifications in regulating diverse biological functions.
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Project description:N7-methylguanosine (m7G) in variable loop region of tRNA stabilizes target tRNA expression, which is catalyzed by METTL1/WDR4 heterodimer. Here, we unveil essential functions of Mettl1 in Drosophila fertility. Mettl1-knockout (Mettl1-KO) decreases elongated spermatid and mature sperm, which is fully rescued by Mettl1-transgene expression, but not catalytic dead Mettl1-transgene, demonstrating that Mettl1-dependent m7G is required for spermatogenesis. Mettl1-KO shows loss of m7G modification on subset of tRNAs and decreased level of tRNA expression. Strikingly, overexpression of translational elongation factor EF1α that can compete with rapid tRNA decay (RTD) pathway in S. cerevisiae, significantly counteract the sterility in Mettl1-KO male, supporting a critical role of m7G tRNA modification in spermatogenesis. Ribo-seq analysis shows that Mettl1-KO elevates ribosome collisions at codons decoded by reduced tRNAs and significantly reduces translation of genes involved in elongated spermatid formation and sperm stability. These findings reveal a developmental role for m7G tRNA modifications and suggest that m7G modification-dependent tRNA stability differs among tissues.
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Project description:We report the identification and quantification of Watson-Crick modifications in tRNA and rRNA through the use of high throughput sequencing. We apply the recently published DM-tRNA-Seq method to generate demethylase treated and untreated 293T samples, and using computational methods we are able to flag sites using a modification index. This index allows us to generate site-resolved information about modification that we can use to identify and quantify Watson-Crick face modifications in tRNA and rRNA. With the demethylase treated samples, we are able to validate numerous nucleotide modifications from demethylase substrates, and the absence of demethylase action also serves to aid in identification. We find numerous novel modification sites in tRNA as well as striking comparisons between tissues cultures lines. Our study reports a comprehensive analysis of the tRNA modification landscape by identifying sites of modification as well as quantifying modification levels.
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Project description:N7-methylguanosine (m7G) modification is one of the most prevalent tRNA modifications in human. The precise function and molecular mechanism of m7G tRNA modification in regulation of cancer remain poorly understood. Here we showed that m7G tRNA modification, METTL1 and WDR4 are elevated in hepatocellular carcinoma (HCC) tissues and associated with HCC patient prognosis. Functionally, silencing METTL1 or WDR4 inhibits HCC cell proliferation, migration and invasion, while forced expression of wild type METTL1 but not its catalytic dead mutant promotes HCC progression. Knockdown of METTL1 reduces m7G tRNA modification and decreases m7G modified tRNA expression. Mechanistically, METTL1 depletion selectively decreases the mRNA translation of a subset of oncogenic genes, especially cell cycle and EGFR pathway genes, in m7G-related codon dependent manner. Moreover, in vivo studies using Mettl1 knock-in and knockout mice reveal a critical function of Mettl1 mediated m7G tRNA modifications in promoting hepatocarcinogenesis in the hydrodynamics transfection HCC model. Our work uncovers the critical functions of tRNA m7G modification in regulating cancer mRNA translation and promoting hepatocarcinogenesis, thus provides new insights into role of the mis-regulated tRNA modifications in cancers.
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