METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA726973 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14407600.fastq.gz | Fastqsanger.gz | |||
| SRR14407601.fastq.gz | Fastqsanger.gz | |||
| SRR14407602.fastq.gz | Fastqsanger.gz | |||
| SRR14407603.fastq.gz | Fastqsanger.gz | |||
| SRR14407604.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 14 |
Similar Datasets
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 | GSE173760 | GEO
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
Project description:The project aims to identify the RNA binding proteins that can specifically bind to mRNA internal modification N7-methylguanosine (m7G). N7-methylguanosine (m7G) methylation has been long identified as the essential cap modification for eukaryotic mRNA, but later has been identified internally in various types of RNAs, including tRNA, rRNA, miRNA, and mRNA. While the METTL1/WDR4 complex, responsible for tRNA m7G installation, has been suggested to be responsible for internal mRNA modification as well, little is known about the proteins that can identify and interact with m7G. To better understand its interaction with RNA binding proteins and further define its regulatory function in mRNA metabolism, we performed the experiment to pulldown proteins with different binding affinity on unmodified G and m7G and subject the enriched fractions to mass spectrometry.
2024-09-03 | PXD049390 | Pride
Project description:The RNA methyltransferase METTL1 catalyzes the N7-methylguanosine (m7G) modification of certain tRNAs, mRNAs, and miRNA precursors. However, the role of METTL1 and its cofactor WDR4 in cancer remains largely unexplored. Here we reveal the oncogenic role of METTL1/WDR4. METTL1 is frequently amplified and overexpressed in cancers and correlates with poor patient survival. METTL1 depletion in human cancer cells causes decreased abundance of m7G-modified tRNAs, altered cell cycle, and inhibits oncogenicity. Strikingly, METTL1/WDR4 overexpression induces oncogenic transformation and carcinogenesis. Mechanistically, we find increased abundance of a subset of m7G-modified tRNAs including tRNA-Arg(TCT), and increased translation of mRNAs enriched in the corresponding AGA codon including cell cycle regulators. Accordingly, expression of tRNA-Arg(TCT) is significantly elevated in many cancer types, correlates with patient survival, and overexpression of this tRNA enhances reporter gene expression and cell transformation. Thus, METTL1/WDR4-mediated m7G tRNA modification drives oncogenic transformation, thereby highlighting METTL1 as a promising cancer therapeutic target.
2020-10-01 | GSE149950 | GEO
Project description:Osteosarcoma is the most common bone tumor that leads to high mortality in adolescents and children. The tRNA N7-methylguanosine methyltransferase METTL1 is located in chromosome 12q14.1, a region that is frequently amplified in osteosarcoma patients, while its functions and underlying mechanisms in regulation of osteosarcoma remain unknown. Herein we show that METTL1 and WDR4 are overexpressed in osteosarcoma and associated with poor patient prognosis. Knockdown of METTL1 or WDR4 causes decreased tRNA m7G modification level and impairs osteosarcoma progression in vitro and in vivo. Conversely, METTL1/WDR4 overexpression promotes osteosarcoma proliferation, migration and invasion capacities. tRNA methylation and mRNA translation profiling indicated that METTL1/WDR4 modified tRNAs enhance translation of mRNAs with more m7G tRNA-decoded codons, including extracellular matrix (ECM) remodeling effectors, which facilitates osteosarcoma progression and chemoresistance to doxorubicin.Our study demonstrates METTL1/WDR4 mediated tRNA m7G modification plays crucial oncogenic functions to enhance osteosarcoma progression and chemoresistance to doxorubicin via alteration of oncogenic mRNA translation, suggesting METTL1 inhibition combined with chemotherapy is a promising strategy for treatment of osteosarcoma patients.
2024-02-01 | GSE225515 | GEO
Project description:The RNA methyltransferase METTL1 catalyzes the N7-methylguanosine (m7G) modification of certain tRNAs, mRNAs, and miRNA precursors. However, the role of METTL1 and its cofactor WDR4 in cancer remains largely unexplored. Here we reveal the oncogenic role of METTL1/WDR4. METTL1 is frequently amplified and overexpressed in cancers and correlates with poor patient survival. METTL1 depletion in human cancer cells causes decreased abundance of m7G-modified tRNAs, altered cell cycle, and inhibits oncogenicity. Strikingly, METTL1/WDR4 overexpression induces oncogenic transformation and carcinogenesis. Mechanistically, we find increased abundance of a subset of m7G-modified tRNAs including tRNA-Arg(TCT), and increased translation of mRNAs enriched in the corresponding AGA codon including cell cycle regulators. Accordingly, expression of tRNA-Arg(TCT) is significantly elevated in many cancer types, correlates with patient survival, and overexpression of this tRNA enhances reporter gene expression and cell transformation. Thus, METTL1/WDR4-mediated m7G tRNA modification drives oncogenic transformation, thereby highlighting METTL1 as a promising cancer therapeutic target.
2020-10-01 | GSE149989 | GEO
Project description:The RNA methyltransferase METTL1 catalyzes the N7-methylguanosine (m7G) modification of certain tRNAs, mRNAs, and miRNA precursors. However, the role of METTL1 and its cofactor WDR4 in cancer remains largely unexplored. Here we reveal the oncogenic role of METTL1/WDR4. METTL1 is frequently amplified and overexpressed in cancers and correlates with poor patient survival. METTL1 depletion in human cancer cells causes decreased abundance of m7G-modified tRNAs, altered cell cycle, and inhibits oncogenicity. Strikingly, METTL1/WDR4 overexpression induces oncogenic transformation and carcinogenesis. Mechanistically, we find increased abundance of a subset of m7G-modified tRNAs including tRNA-Arg(TCT), and increased translation of mRNAs enriched in the corresponding AGA codon including cell cycle regulators. Accordingly, expression of tRNA-Arg(TCT) is significantly elevated in many cancer types, correlates with patient survival, and overexpression of this tRNA enhances reporter gene expression and cell transformation. Thus, METTL1/WDR4-mediated m7G tRNA modification drives oncogenic transformation, thereby highlighting METTL1 as a promising cancer therapeutic target.
2020-10-01 | GSE149970 | GEO
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.
2021-06-26 | GSE174492 | GEO
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
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 homozygous mutated WDR4 caused microcephaly, retardation in motor coordination and spatial learning ability in mice, which mimics the symptom in human patients with WDR4 mutation. Further analysis revealed that homozygous mutation of WDR4 impaired tRNA m7G modification and reduced the translation level of genes involved in mTOR signaling pathway in mouse brain, which further caused endoplasmic reticulum (ER) stress and cell death. 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 neuron disorders.
2024-10-16 | GSE229610 | GEO