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The tRNA methyltransferase Mettl1 governs ketogenesis through translational regulation and drives metabolic reprogramming in cardiomyocyte maturation

ABSTRACT: The tRNA methyltransferase Mettl1 governs ketogenesis through translational regulation and drives metabolic reprogramming in cardiomyocyte maturation

PROVIDER: PRJNA1095927 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28548407.fastq.gz	Fastqsanger.gz
	SRR28548408.fastq.gz	Fastqsanger.gz
	SRR28548409.fastq.gz	Fastqsanger.gz
	SRR28548410.fastq.gz	Fastqsanger.gz
	SRR28548411_1.fastq.gz	Fastqsanger.gz

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The tRNA methyltransferase Mettl1 governs ketogenesis through translational regulation and drives metabolic reprogramming in cardiomyocyte maturation

Project description:Following birth, the heart undergoes intricate transitions in response to the altered environment, including shifts in energy metabolism and cytoarchitecture, such as the switch from glucose to lipid utilization and the transformation of fetal-to-adult sarcomeric gene isoforms, all aimed at achieving functional maturation. These adaptations facilitate efficient energy production and cardiac contraction, enabling the heart to effectively pump blood throughout the body. Although the early postnatal period is widely recognized as a critical phase for cardiomyocyte maturation, the precise mechanisms initiating and orchestrating this process remain elusive. Using in vivo and in vitro models incorporated with multi-omic analyses, we here show that Mettl1 is a critical regulator in postnatal cardiomyocyte maturation. We demonstrate that Mettl1 is required for the proper ketogenesis in cardiomyocyte maturation via regulating Hmgcs2 translation. Loss of Mettl1 leads to aberrant metabolic reprogramming and subsequent cardiomyocyte immaturation through the deficiency in lysine β-hydroxybutyrylation of TCA cycle-related proteins.

2024-10-13 | GSE263137 | GEO

A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation

Project description:Data supporting the manuscript: A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation

2024-11-05 | MSV000096296 | MassIVE

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

METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer

Project description:Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of cancer; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5’tRNA fragments. 5′ tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy, leading to decreased tumour progression. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translational control and tumour biology.

2023-08-08 | GSE230694 | GEO

Competitive regulation of HOPX transcription governs cardiomyocyte maturation

Project description:Competitive regulation of HOPX transcription governs cardiomyocyte maturation

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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 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

METTL1/WDR4 mediated tRNA N7-methylguanosine (m7G) modifications promote mRNA translation and lung cancer progression [TRAC-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 | GSE173760 | GEO

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

2022-12-31 | GSE173750 | GEO