Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

M7G Trac-Seq analysis in MEF Wt cells overexpressing METTL1+WDR4

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE149950 | GEO | 2020/10/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

m7G Trac-Seq analysis in LNZ308 METTL1 knockdown cells

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

Ribosome Footprinting (RiboSeq) analysis of mRNA translation in MEF Wt cells overexpressing METTL1+WDR4

2020-10-01 | GSE149970 | GEO

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

N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis

Project description:The cancer cells selectively promote the translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. 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 esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. Functionally, depletion of METTL1 or WDR4 suppresses proliferation, migration, and invasion of ESCC cells. In addition, forced expression of METTL1 or WDR4 promotes ESCC 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 mTOR signaling and autophagy in m7G related codon dependent manner. Rescue assays revealed the essential function of RPTOR/ULK1/autophagy axis in METTL1 driven ESCC progression. Furthermore, ESCC initiation and progression models using Mettl1 conditional knockout and knockin mice uncovered the strong physiological function of Mettl1 in promoting in vivo ESCC tumorigenesis. 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 and its downstream signaling axis could be a promising strategy for ESCC treatment.

2022-02-16 | GSE169590 | GEO

METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promotes oncogenesis and doxorubicin resistance in osteosarcoma

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

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 promotes hepatocarcinogenesis via m7G tRNA modification dependent translation control

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

Mettl1-dependent m7G tRNA modification is essential for maintaining fertility and proper spermatogenesis in Drosophila melanogaster

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.

2024-08-16 | GSE241519 | GEO

The m7G tRNA methylome regulates 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 are 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.

2018-07-01 | GSE112670 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data