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M1A methylase TRMT6 promotes neuroblastoma development by demethylating SST mRNA in an m1A/YTHDF2-dependent manner

ABSTRACT: m1A, a prevalent RNA modification found in various RNA species, was recently reported to modulate cancer progression; However its effects in neuroblastoma have not been investigated. In this study, we observed a significantly elevated expression of m1A transmethylase TRMT6 in high-risk and late-stage neuroblastoma patients. Silence and regain of function studies demonstrated that TRMT6 promotes neuroblastoma cell malignancy, tumor growth, and metastasis in vitro and in vivo. Omics analysis and cancer malignancy assay revealed that somatostatin (SST) is the functional downstream target of TRMT6, which determined the pro-tumor role of TRMT6 in neuroblastoma. Mechanistically, TRMT6 reduces SST mRNA levels by inhibiting its mRNA stability in an m1A-YTHDF2-dependent manner, which revealed the crosstalk of the m1A methylase TRMT6 in neuroblastoma. Moreover, SST analog octreotide suppresses neuroblastoma cell malignancy, tumor growth, and metastasis. Targeting TRMT6 provides a novel potential diagnosis and therapeutic target for neuroblastoma

ORGANISM(S): Homo sapiens

PROVIDER: GSE297545 | GEO | 2025/12/01

REPOSITORIES: GEO

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m1A methylase TRMT6 promotes neuroblastoma development by demethylating SST mRNA in an m1A/YTHDF2-dependent manner

Project description:m1A methylase TRMT6 promotes neuroblastoma development by demethylating SST mRNA in an m1A/YTHDF2-dependent manner

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TRMT6-mediated tRNA m1A modification serves as a translational checkpoint of histone biosynthesis and facilitates colorectal cancer progression [RNA]

Project description:Reprogramming of mRNA translation drives malignant transformation and cancer development. Recently, increasing studies have demonstrated that tRNA modification emerges as a critical regulator of translational reprogramming; however, its function in cancers remains largely elusive. Herein, we identify the oncogenic role of tRNA N1-methyladenosine (m1A) modification in colorectal cancer (CRC). Targeting m1A methyltransferase TRMT6 in CRC cells decreases the abundance of a specific subset of tRNAs (e.g., tRNA-Arg-ACG-1-1, tRNA-Lys-TTT-1-1) and impairs histone mRNA translation in a codon-biased manner, thus restricting histone biosynthesis and cell cycle progression. We further demonstrate that the combination of TRMT6 inhibition and CDK4/6 inhibition shows a stronger anti-cancer effect on CRC cells by synergistically inhibit histone biosynthesis. Collectively, our study reveals that tRNA m1A modification acts as a translational checkpoint of histone biosynthesis and promotes CRC progression, providing new insights for the development of efficient therapeutic strategies against CRC.

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TRMT6-mediated tRNA m1A modification serves as a translational checkpoint of histone biosynthesis and facilitates colorectal cancer progression [tRNA]

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TRMT6-mediated tRNA m1A modification serves as a translational checkpoint of histone biosynthesis and facilitates colorectal cancer progression [Ribo]

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Gene-silencing activity of small RNAs controlled by TRMT6/61A-dependent base methylation

Project description:We identified human small RNAs containing m1A (N1-methyladenosine) by m1A RIP and TGIRT-seq. Small RNA-seq and long RNA-seq was performed after TRMT6/61A knock-down.

2022-02-09 | GSE171040 | GEO

Project description:We reported the tRNA-m1A sequencing results performed in young and aged hematopoietic stem and progenitor cells. Our results defined aging-associated alterations of tRF in hematopoietic stem and progenitor cells and identifed a subset of tRF as hallmark of HSC aging.RNA-seq data analysis of WT v.s. Trmt6/61a-TG hematopoietic stem cell (lineage-, c-kit+ Sca-1+ CD135-, CD34-), the two population of hematopoietic stem cell (HSC) were purified from the bone marrow of WT and Trmt6/61a-TG mice, revealed that differnent expression of WT v.s. Trmt6/61a-TG hematopoietic stem cell.Results provide insight into the role of TRMT6/61A complex in HSC.

2024-01-18 | GSE163301 | GEO

Chemical manipulation of m1A mediates its detection in human tRNA

Project description:N1-methyl adenosine (m1A) is a wide-spread RNA modification present in tRNA, rRNA and mRNA. m1A modification sites in tRNAs are evolutionary conserved and its formation on tRNA is catalyzed by methyltransferase TRMT61A and TRMT6 complex. m1A promotes translation initiation and elongation. Due to its positive charge under physiological conditions, m1A can notably modulate RNA structure. It also blocks Watson-Crick base pairing and causes mutation and truncation during reverse transcription. Several misincorporation-based high throughput sequencing methods have been developed to sequence m1A. In this study, we introduce a reduction-based m1A sequencing (red-m1A-seq). We report that NaBH4 reduction of m1A can improve the mutation and readthrough rates using commercially available RT enzymes to give better positive signature, while alkaline-catalyzed Dimroth rearrangement can efficiently convert m1A to m6A to provide good controls, allowing the detection of m1A with higher sensitivity and accuracy. We applied red‑m1A-seq to sequence human small RNA and we not only detected all the previously reported tRNA m1A sites, but also new m1A sites in mt-tRNAAsn-ATT and 5.8S rRNA.

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tRNA m1A modification regulate hematopoietic stem cell maintenance via mTORC1 signaling [scRNA-seq]

Project description:Hematopoietic stem cells (HSCs) have some unique physiological adaptations to maintain blood cell production and deal with stress responses throughout life. To maintain such adaptations, HSCs are particularly dependent on maintaining a tightly controlled protein translation rate. However, how HSCs fine tune protein translation has not been fully described. In this study, we report the role of TRMT6 in regulating HSC function in adult hematopoiesis. Trmt6-null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow 4 to 8 weeks after Trmt6 deletion. Trmt6-deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Loss of TRMT6 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, mTORC1 signaling pathway was highly upregulated in HSC-enriched cell populations after Trmt6 deletion by single cell RNA-seq analysis. Furthermore, TRMT6 was required for tRNA m1A modification required for HSC quiescence and self-renewal. Our data indicate that TRMT6 promotes the expression of TSC1, fine-tuning mTORC1 signaling level which is essential for HSC maintenance and self-renewal in adult hematopoiesis.

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Reversible and Dynamic m1A Methylation in the Human Transcriptome

Project description:N1-methyladenosine (m1A) is an abundant post-transcriptional RNA modification, yet little is known about its prevalence, topology and dynamics in mRNA. Here, we show that m1A is abundant in human mRNA, with an m1A/A ratio of ~0.02%. We develop m1A-ID-Seq, based on m1A immunoprecipitation and the inherent property of m1A to stall reverse transcription, for the transcriptome-wide m1A analysis. m1A-ID-Seq identifies 901 m1A peaks (from 583 genes) in mRNA and ncRNA, and reveals a prominent feature of enrichment in the 5â-untranslated region of mRNA transcripts, distinct from that of N6-methyladenosine, the most abundant internal mammalian mRNA modification. m1A in mRNA is also reversible by ALKBH3, a known DNA/RNA demethylase. Lastly, m1A responds dynamically to stimuli and hundreds of stress-induced m1A sites are identified. Collectively, our approaches allow comprehensive analysis of m1A methylation and provide an important tool for functional studies of potential epigenetic regulation via the reversible and dynamic m1A methylation. Identification of m1A sites in human embryonic kidney cells. Comparisons of m1A profiles of wild type HEK293T with ALKBH3 knock out cell line reveals the ALKBH3 specific sites. Stress inducible m1A sites are also identified by comparing the profiles of untreated cells with stress treated cells.

2016-02-05 | E-GEOD-73941 | biostudies-arrayexpress

N1-methyladenosine methylations in tRNA drive liver tumorigenesis by PPARδ-mediated cholesterol synthesis

Project description:Increased protein translation plays a critical role in cancer development and treatment1,2. However, the molecular mechanism that is involved in this process remains poorly understood. N1-methyladenosine (m1A) methylation in RNA accounts for regulating mRNA translation in a post-transcriptional manner3,4. Here we show that m1A methylation levels are remarkably elevated in hepatocellular carcinoma (HCC) patient tumor tissues, especially in patients with microscopic vascular invasion (MVI). Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. Consistently, TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumors and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylations are required for self-renewal of liver CSCs and tumorigenesis. Mechanistically, TRMT6/TRMT61A-dependent m1A in tRNA boost PPARδ expression, which triggers cholesterol synthesis to activate Hedgehog signaling, driving self-renewal of liver CSCs and tumorigenesis. For potential therapeutic benefit, we further identify a specific inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer with high m1A methylations. Our findings provide novel insights into the function and molecular mechanism of m1A modifications underlying liver tumorigenesis and drug target, which will serve as a new biomarker for HCC and pave a new way to develop more effective therapeutic strategies for HCC patients.

2021-03-01 | GSE147840 | GEO

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