Coordination of mRNA and tRNA methylations by TRMT10A
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA609703 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11214551.fastq.gz | Fastqsanger.gz | |||
| SRR11214552.fastq.gz | Fastqsanger.gz | |||
| SRR11214553.fastq.gz | Fastqsanger.gz | |||
| SRR11214554.fastq.gz | Fastqsanger.gz | |||
| SRR11214555.fastq.gz | Fastqsanger.gz |
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Project description:The post-transcriptional modification of mRNA and tRNA provides an additional layer of regulatory complexity during gene expression. TRMT10A is a tRNA methyltransferase that installs N1-methylguanosine (m1G), while FTO performs demethylation on N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) in mRNA. We find that this tRNA methyltransferase TRMT10A interacts with mRNA demethylase FTO (ALKBH9), both in vitro and inside cells. Strikingly, depletion of TRMT10A not only led to decreased m1G in tRNA but also significantly increased m6A levels in mRNA. CLIP-seq results showed that TRMT10A shares a significant overlap of associated mRNAs with FTO, and these mRNAs have accelerated decay rates potentially through the regulation by specific m6A reader. Furthermore, transcripts with increased m6A upon TRMT10A ablation contain an overrepresentation of m1G9-containing tRNAs codons read by tRNAGln(TTG), tRNAArg(CCG), and tRNAThr(CGT). These findings collectively reveal the presence of coordinated mRNA and tRNA modifications and demonstrate a mechanism for regulating gene expression through the interactions between mRNA and tRNA modifying enzymes.
2020-04-22 | GSE146207 | GEO
Project description:The posttranscriptional modification of messenger RNA (mRNA) and transfer RNA (tRNA) provides an additional layer of regulatory complexity during gene expression. Here, we show that a tRNA methyltransferase, TRMT10A, interacts with an mRNA demethylase FTO (ALKBH9), both in vitro and inside cells. TRMT10A installs N 1-methylguanosine (m1G) in tRNA, and FTO performs demethylation on N 6-methyladenosine (m6A) and N 6,2'-O-dimethyladenosine (m6Am) in mRNA. We show that TRMT10A ablation not only leads to decreased m1G in tRNA but also significantly increases m6A levels in mRNA. Cross-linking and immunoprecipitation, followed by high-throughput sequencing results show that TRMT10A shares a significant overlap of associated mRNAs with FTO, and these mRNAs have accelerated decay rates potentially through the regulation by a specific m6A reader, YTHDF2. Furthermore, transcripts with increased m6A upon TRMT10A ablation contain an overrepresentation of m1G9-containing tRNAs codons read by tRNAGln(TTG), tRNAArg(CCG), and tRNAThr(CGT) These findings collectively reveal the presence of coordinated mRNA and tRNA methylations and demonstrate a mechanism for regulating gene expression through the interactions between mRNA and tRNA modifying enzymes.
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Project description:Increased protein translation plays a critical role in cancer development and treatment1,2. However, the molecular mechanism that is involved in this process remains poorly understood. N1-methyladenosine (m1A) methylation in RNA accounts for regulating mRNA translation in a post-transcriptional manner3,4. Here we show that m1A methylation levels are remarkably elevated in hepatocellular carcinoma (HCC) patient tumor tissues, especially in patients with microscopic vascular invasion (MVI). Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. Consistently, TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumors and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylations are required for self-renewal of liver CSCs and tumorigenesis. Mechanistically, TRMT6/TRMT61A-dependent m1A in tRNA boost PPARδ expression, which triggers cholesterol synthesis to activate Hedgehog signaling, driving self-renewal of liver CSCs and tumorigenesis. For potential therapeutic benefit, we further identify a specific inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer with high m1A methylations. Our findings provide novel insights into the function and molecular mechanism of m1A modifications underlying liver tumorigenesis and drug target, which will serve as a new biomarker for HCC and pave a new way to develop more effective therapeutic strategies for HCC patients.
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Project description:N1-methyladenosine methylations in tRNA drive liver tumorigenesis by PPARδ-mediated cholesterol synthesis
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Project description:Although messenger RNA (mRNA) vaccines have been employed to prevent the spread of COVID-19, they are critically limited by instability and low translation capacity. Alterations in tRNA abundance and modification, associated with codon optimality, impact mRNA stability and protein output in a codon-dependent manner, implying tRNA as a potential translation enhancer. Here, we report a strategy named tRNA-plus to augment translation based on artificially modulating the tRNA availability. We demonstrated that overexpression of specific tRNAs enhanced the stability and translation efficiency of SARS-CoV-2 Spike mRNA, resulting in substantial improvements in protein levels by up to 4.7-fold. In addition, chemically synthesized tRNAs bearing multiple site-specific modifications, particularly at the anticodon loop and TΨC-loop, exhibited an average of ~4-fold higher decoding efficacy than unmodified tRNA, along with increased stability and reduced immune toxicity. We further leveraged an optimized lipid nanoparticles (LNP) system for codelivery of Spike mRNA vaccine and tRNA, which elicited enhanced spike-specific humoral and cellular immune responses in vivo. The methods presented here may become a general approach for elevating mRNA translation potency, which can be applied to various translation-based fields.
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Project description:Despite its biological importance, transfer RNA (tRNA) could not be adequately sequenced due to the abundant presence of post-transcriptional modifications and extensive structure that interfere with cDNA synthesis and adapter ligation. We achieve efficient and quantitative tRNA sequencing by removing base methylations using engineered demethylases and using a highly processive thermo-stable reverse transcriptase without the need for adapter ligation (DMTRT-tRNA-seq). Our method should be applicable for biological investigations of tRNA in all organisms.
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Project description:Oligodendrocytes are specialized cells that confer neuronal myelination. Leukodystrophies associated with oligodendrocyte and hypomyelination are known to result when a number of tRNA metabolism genes are mutated. Thus, for unknown reasons, oligodendrocytes may be hypersensitive to perturbations in tRNA biology. In this study, we survey the tRNA transcriptome in the murine oligodendrocytes cell lineage in an effort to understanding the molecular underpinning for human disease. We find that specific tRNAs are hypomodified in oligodendrocytes within or near the anticodon. This hypomodified state may be the result of differential expression of key modification enzymes during oligodendrocyte differentiation. Moreover, we observe a concomitant relationship between tRNA hypomodification and tRNA decoding potential; observing oligodendrocyte specific alterations in codon optimality-mediated mRNA decay and ribosome transit. Our results reveal that oligodendrocytes naturally maintain a delicate, hypersensitized tRNA/mRNA axis. We suggest this axis underlies disease etiology when further insult to tRNA metabolism is introduced.
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Project description:Oligodendrocytes are specialized cells that confer neuronal myelination. Leukodystrophies associated with oligodendrocyte and hypomyelination are known to result when a number of tRNA metabolism genes are mutated. Thus, for unknown reasons, oligodendrocytes may be hypersensitive to perturbations in tRNA biology. In this study, we survey the tRNA transcriptome in the murine oligodendrocytes cell lineage in an effort to understanding the molecular underpinning for human disease. We find that specific tRNAs are hypomodified in oligodendrocytes within or near the anticodon. This hypomodified state may be the result of differential expression of key modification enzymes during oligodendrocyte differentiation. Moreover, we observe a concomitant relationship between tRNA hypomodification and tRNA decoding potential; observing oligodendrocyte specific alterations in codon optimality-mediated mRNA decay and ribosome transit. Our results reveal that oligodendrocytes naturally maintain a delicate, hypersensitized tRNA/mRNA axis. We suggest this axis underlies disease etiology when further insult to tRNA metabolism is introduced.
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Project description:Although messenger RNA (mRNA) vaccines have been employed to prevent the spread of COVID-19, they are critically limited by instability and low translation capacity. Alterations in tRNA abundance and modification, associated with codon optimality, impact mRNA stability and protein output in a codon-dependent manner, implying tRNA as a potential translation enhancer. Here, we report a strategy named tRNA-plus to augment translation based on artificially modulating the tRNA availability. We demonstrated that overexpression of specific tRNAs enhanced the stability and translation efficiency of SARS-CoV-2 Spike mRNA, resulting in substantial improvements in protein levels by up to 4.7-fold. In addition, chemically synthesized tRNAs bearing multiple site-specific modifications, particularly at the anticodon loop and TΨC-loop, exhibited an average of ~4-fold higher decoding efficacy than unmodified tRNA, along with increased stability and reduced immune toxicity. We further leveraged an optimized lipid nanoparticles (LNP) system for codelivery of Spike mRNA vaccine and tRNA, which elicited enhanced spike-specific humoral and cellular immune responses in vivo. The methods presented here may become a general approach for elevating mRNA translation potency, which can be applied to various translation-based fields.
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