Undefined
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB49285 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| ERR7625430_1.fastq.gz | Fastqsanger.gz | |||
| ERR7625430_2.fastq.gz | Fastqsanger.gz | |||
| ERR7625440_1.fastq.gz | Fastqsanger.gz | |||
| ERR7625440_2.fastq.gz | Fastqsanger.gz |
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Project description:Guanosine-7 tRNA methylation steers tRNA-derived fragment biogenesis and translational control in prostate cancer
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Project description:Guanosine-7 tRNA methylation steers tRNA-derived fragment biogenesis and translational control in prostate cancer
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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
Project description:Abstract Transfer RNAs (tRNAs) are exceptionally subject to modifications, including methylation. While mRNA methylation is emerging as an important regulator of biological and pathological processes in cancer, how post-transcriptional methylation of tRNAs contributes to cancer is largely unknown. Here we show that the RNA N7-methylguanosine (m7G) methyltransferase METTL1 is highly differentially expressed in prostate cancer compared to non-tumour prostate tissues. METTL1 expression regulation is mediated by the oncogenic regulator PI3K, which is altered in most advanced prostate tumours. Knockdown of METTL1 dramatically inhibits prostate cancer cell growth and tumour progression in vivo. In contrast, overexpression of the wild type but not the catalytically inactive METTL1 potentiates cell growth. Thus, METTL1-mediated methylation is important for prostate tumorigenesis. Mechanistically we find that METTL1 depletion causes loss of m7G tRNA methylation and increases endonucleolytic cleavage of Cysteine tRNA leading to an accumulation of 5′ tRNA-derived small RNA fragments. 5′ tRNA-derived fragments steer translation control to favour synthesis of key regulators of tumour growth suppression and immune rejection. In summary, our findings uncover a critical function of m7G tRNA methylation in directing translation control in cancer cells with important implications for tumour growth and unveil METTL1 inhibition as a promising anti-cancer therapeutic strategy. induction and maintenance of naïve human pluripotency are governed by distinct signaling requirements. tRNAs from WT and METTL1 KO cells were subjected to NaBH4-Aniline treatment followed by RNA-seq to unveil methylation of guanosine-7 in tRNA with nucleotie resolution. RNA-seq libraries were also analysed to unveil tRNA stability or processing into tRNA-derived fragments in METTL1 KO cells.
2023-08-08 | GSE190911 | GEO
Project description:METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer
| PRJNA962138 | ENA
Project description:Transfer RNAs (tRNAs) are exceptionally subject to modifications, including methylation. While mRNA methylation is emerging as an important regulator of biological and pathological processes in cancer, how post-transcriptional methylation of tRNAs contributes to cancer is largely unknown. Here we show that the RNA N7-methylguanosine (m7G) methyltransferase METTL1 is highly differentially expressed in prostate cancer compared to non-tumour prostate tissues. METTL1 expression regulation is mediated under the oncogenic PI3K-PTEN pathway. Knockdown of METTL1 dramatically inhibits prostate cancer cell growth and tumour progression in vivo. In contrast, overexpression of the wild type but not the catalytically inactive METTL1 potentiates cell growth. Thus, METTL1-mediated methylation is important for prostate tumorigenesis. Mechanistically we find that METTL1 depletion causes loss of m7G tRNA methylation and increases endonucleolytic cleavage of tRNA leading to an accumulation of 5′ tRNA-derived small RNA fragments. 5′ tRNA-derived fragments steer translation control to favour synthesis of key regulators of tumour growth suppression and immune rejection. In summary, our findings uncover a critical function of m7G tRNA methylation in directing translation control in cancer cells with important implications for tumour growth and unveil METTL1 inhibition as a promising anti-cancer therapeutic strategy.
2023-10-24 | PXD030141 | Pride
Project description:Combining transcriptome-wide approaches to detect m7G RNA methylation, in vitro functional assays and Mettl1 knockout mouse models, we provide evidence that guanosine-7 tRNA methylation is required to protect tRNAs from cleavage in response to stress, leading to impaired regulation of protein synthesis. Loss of METTL1 and tRNA methylation sensitises cancer cells to stress, reducing tumour growth and increasing cytotoxic responses to convectional cancer treatments in vitro and in vivo. Our study uncovers the role of m7G methylation of tRNAs in stress responses and highlights the potential of targeting METTL1 to sensitise cancer cells to therapy.
2024-01-26 | PXD036009 | Pride
Project description:Methyl-5-uridine (m5U) is one of the most abundant RNA modifications found in cytosolic tRNA. tRNA methyltransferase 2 homolog A (hTRMT2A) is the dedicated mammalian enzyme of m5U conversion at tRNA position 54. However, its RNA binding specificity and functional role in the cell are not well understood. Here we dissected structural and sequence requirements for binding and methylation of its RNA targets. Specificity of tRNA modification by TRMT2A is achieved by a combination of modest binding preference and presence of a uridine in position 54 of tRNAs. Mutational analysis together with crosslinking experiments identified a large hTRMT2A-tRNA binding surface. Furthermore, complementing hTRMT2A interactome studies revealed that TRMT2A interacts with proteins involved in both tRNA and rRNA biogenesis. Consistent with this finding, we observed that TRMT2A not only methylates tRNA, but also rRNA. Finally, we addressed the question of the importance of TRMT2A function by showing that its knockdown reduces translational fidelity. These findings extend the role of hTRMT2A beyond tRNA modification towards rRNA biogenesis and translational fidelity.
2023-07-04 | PXD036538 | Pride
Project description:Pseudouridylation (Ψ) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of Ψ remains poorly understood. Here, we show that a Ψ-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the Ψ ‘writer’ PUS7 modifies and activates a network of tRNA-derived fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translational regulation leading to increased protein biosynthesis and abnormal germ layer specification. Remarkably, dysregulation of PUS7 and tRFs in myeloid malignancies associates with altered translation rates, suggesting a role of Ψ in leukemogenesis. Our findings unveil a critical function of Ψ in directing translational control in stem cells with important implications for human disease.
2018-04-11 | PXD008676 | Pride
Project description:Pseudouridylation (pseudouridine) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of pseudouridine remains poorly understood. Here, we show that a pseudouridine-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the pseudouridine ‘writer’ PUS7 modifies and activates a network of tRNA-derived fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translational regulation leading to high protein biosynthesis and abnormal germ layer specification. Dysregulation of PUS7 and tRFs in myeloid malignancies associates with altered translation rates, suggesting a role of pseudouridine in tumorigenesis. Our findings unveil a critical function of pseudouridine in directing translational control in stem cells with promisingly broad implications for human disease.
2018-04-09 | GSE101485 | GEO