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METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173761 | GEO | 2022/12/31

REPOSITORIES: GEO

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METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression [RNA-seq]

Project description:The tRNA N7-methylguanosine (m7G) modification is not essential for yeast growth, but in mammals mis-regulations of tRNA m7G modification cause stem cell defect and developmental disorders. Here we found that tRNA m7G methyltransferase complex components METTL1 and WDR4 are elevated in lung cancer tissues and associated with poor lung cancer prognosis. Functionally, depletion of METTL1 or WDR4 suppresses proliferation, migration, and invasion of lung cancer cells. In addition, forced expression of METTL1 or WDR4 promotes lung cancer progression depending on the tRNA m7G methyltransferase activity. Mechanistically, METTL1 knockdown leads to reduced tRNA m7G modification and decreased expression of m7G-modified tRNAs. Depletion of METTL1 selectively reduces the translation of a subset of oncogenic transcripts, including the genes related to cell proliferation in a m7G related codon dependent manner. Our study uncovered a new layer of translation regulation mechanism mediated by tRNA m7G modification, provided strong evidence to support the important physiological function of mis-regulated tRNA modification in cancer, and suggested that targeting METTL1 could be a promising strategy for lung cancer treatment.

2022-12-31 | GSE173750 | GEO

METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression [TRAC-seq]

2022-12-31 | GSE173760 | GEO

Structural insight into how WDR4 promotes the tRNA N7-methylguanosine methyltransferase activity of METTL1.

Project description: Not available

| S-EPMC10300002 | biostudies-literature

Aberrant translation regulation by METTL1/WDR4-mediated tRNA N7-methylguanosine modification drives HNSCC progression

Project description:The cancer cells selectively promote the translation of specific oncogenic transcripts to stimulate cancer progression. Although growing evidence has revealed that tRNA modifications and related genes participate in this process, their roles in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized. Here we found that tRNA m7G methyltransferase complex components METTL1/WDR4 were both upregulated in HNSCC and associated with poor prognosis. Functionally, METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models. Mechanistically, ablation of METTL1 reduced m7G levels of 16 tRNAs, causing translational inhibition of a subset of oncogenic transcripts, including the genes related to PI3K/AKT/mTOR signaling pathway. In addition, chemical modulators of PI3K/AKT/mTOR signaling pathway can reverse the effects of Mettl1 in HNSCC. Furthermore, single-cell RNA sequencing results revealed that depletion of Mettl1 in tumor cells altered the immune landscape and cell-cell interaction between tumor and stromal compartment. In summary, this study uncovered the physiological function and mechanism of mis-translation regulation mediated by tRNA m7G modification in HNSCC, and suggested that targeting METTL1 could be a promising treatment strategy for HNSCC patients.

2022-03-23 | GSE172146 | GEO

METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression

Project description:METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression

| PRJNA726973 | ENA

METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression [RNA-seq]

Project description:METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression [RNA-seq]

| PRJNA726963 | ENA

METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression [TRAC-seq]

Project description:METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression [TRAC-seq]

| PRJNA726975 | ENA

METTL1/WDR4-mediated m<sup>7</sup>G tRNA modifications and m<sup>7</sup>G codon usage promote mRNA translation and lung cancer progression.

Project description:Mis-regulated epigenetic modifications in RNAs are associated with human cancers. The transfer RNAs (tRNAs) are the most heavily modified RNA species in cells; however, little is known about the functions of tRNA modifications in cancers. In this study, we uncovered that the expression levels of tRNA N7-methylguanosine (m7G) methyltransferase complex components methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) are significantly elevated in human lung cancer samples and negatively associated with patient prognosis. Impaired m7G tRNA modification upon METTL1/WDR4 depletion resulted in decreased cell proliferation, colony formation, cell invasion, and impaired tumorigenic capacities of lung cancer cells in vitro and in vivo. Moreover, gain-of-function and mutagenesis experiments revealed that METTL1 promoted lung cancer growth and invasion through regulation of m7G tRNA modifications. Profiling of tRNA methylation and mRNA translation revealed that highly translated mRNAs have higher frequencies of m7G tRNA-decoded codons, and knockdown of METTL1 resulted in decreased translation of mRNAs with higher frequencies of m7G tRNA codons, suggesting that tRNA modifications and codon usage play an essential function in mRNA translation regulation. Our data uncovered novel insights on mRNA translation regulation through tRNA modifications and the corresponding mRNA codon compositions in lung cancer, providing a new molecular basis underlying lung cancer progression.

| S-EPMC8636169 | biostudies-literature

Detection of internal N7-methylguanosine (m7G) RNA modifications by mutational profiling sequencing.

Project description:Methylation of guanosine on position N7 (m7G) on internal RNA positions has been found in all domains of life and have been implicated in human disease. Here, we present m7G Mutational Profiling sequencing (m7G-MaP-seq), which allows high throughput detection of m7G modifications at nucleotide resolution. In our method, m7G modified positions are converted to abasic sites by reduction with sodium borohydride, directly recorded as cDNA mutations through reverse transcription and sequenced. We detect positions with increased mutation rates in the reduced and control samples taking the possibility of sequencing/alignment error into account and use replicates to calculate statistical significance based on log likelihood ratio tests. We show that m7G-MaP-seq efficiently detects known m7G modifications in rRNA with mutational rates up to 25% and we map a previously uncharacterised evolutionarily conserved rRNA modification at position 1581 in Arabidopsis thaliana SSU rRNA. Furthermore, we identify m7G modifications in budding yeast, human and arabidopsis tRNAs and demonstrate that m7G modification occurs before tRNA splicing. We do not find any evidence for internal m7G modifications being present in other small RNA, such as miRNA, snoRNA and sRNA, including human Let-7e. Likewise, high sequencing depth m7G-MaP-seq analysis of mRNA from E. coli or yeast cells did not identify any internal m7G modifications.

| S-EPMC6847341 | biostudies-literature

Mettl1/Wdr4-Mediated m7G tRNA Methylome Is Required for Normal mRNA Translation and Embryonic Stem Cell Self-Renewal and Differentiation.

Project description:tRNAs are subject to numerous modifications, including methylation. Mutations in the human N7-methylguanosine (m7G) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and brain malformation, yet the molecular and cellular function in mammals is not well understood. We developed m7G methylated tRNA immunoprecipitation sequencing (MeRIP-seq) and tRNA reduction and cleavage sequencing (TRAC-seq) to reveal the m7G tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs is modified at a "RAGGU" motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs, implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian m7G tRNA methylome and highlights its essential role in ESCs with links to human disease.

| S-EPMC6086580 | biostudies-literature

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