Coordination of mRNA and tRNA methylations by TRMT10A
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ABSTRACT:
PROVIDER: PRJNA609703 | ENA |
REPOSITORIES: ENA
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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: Not available
| S-EPMC7149399 | biostudies-literature
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.
2021-03-01 | GSE147840 | GEO
Project description:N1-methyladenosine methylations in tRNA drive liver tumorigenesis by PPARδ-mediated cholesterol synthesis
| PRJNA622261 | ENA
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.
2015-07-01 | GSE66550 | GEO
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.
2022-08-08 | GSE182808 | GEO
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.
2022-08-08 | GSE198271 | GEO
Project description:rs14-01_mitomanip2 - microarray experiment 4 - Mitochondrial transcriptome regulation and coordination with the nucleus - Following a previously established strategy (Val et al., 2011, Nucleic Acids Res. 39, 9262–9274), we express, from an estradiol-inducible nuclear transgene, a trans-cleaving ribozyme directed against the nad9 mitochondrial mRNA and associated as a trailor sequence to a tRNA mimic. The latter serves as a shuttle and ensures mitochondrial uptake of the chimeric RNA through the natural tRNA import pathway. In mitochondria, the ribozyme triggers cleavage and degradation of the target mRNA. The impact of the nad9 mRNA knockdown on the overall plant transcriptome is analyzed over 4 successive days. Control plants express the shuttle RNA combined with a ribozyme that has no specific target in A. thaliana.
2017-01-05 | GSE93122 | GEO
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.
2022-08-08 | GSE182810 | GEO
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.
2022-08-08 | GSE182809 | GEO