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Study on the Mechanism of m5C Methyltransferase NSUN3 Remodeling the Glioma Immune Microenvironment by Driving Tunneling Nanotube-Mediated Mitochondrial Transfer via tRNA Modification [RNA-Seq]

ABSTRACT: Glioma is the most common and aggressive malignant tumor in the central nervous system, and its immunosuppressive microenvironment is closely associated with therapeutic resistance and poor prognosis. NSUN3, an m5C methyltransferase, catalyzes m5C modification on tRNA and regulates RNA translation and cellular metabolism. However, the role and transcriptomic mechanism of NSUN3 in remodeling the glioma immune microenvironment remain unclear. In this study, mRNA sequencing was performed on NSUN3-knockdown glioma cells and control cells to identify differentially expressed mRNAs and related signaling pathways. Total RNA was extracted, and mRNA was enriched for library construction and high-throughput sequencing. Bioinformatics analyses including quality control, read mapping, gene quantification, differential expression screening, and functional enrichment (GO, KEGG, GSEA) were conducted. We identified a series of differentially expressed mRNAs associated with tRNA modification, mitochondrial transfer, tunneling nanotube formation, and immune regulation. These mRNAs were significantly enriched in immune response, cellular metabolism, and tumor progression pathways. Our transcriptomic data provide a comprehensive resource for understanding the mechanism by which NSUN3 drives tunneling nanotube-mediated mitochondrial transfer and remodels the glioma immune microenvironment, and offer potential targets for glioma immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330074 | GEO | 2026/05/11

REPOSITORIES: GEO

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Study on the Mechanism of m5C Methyltransferase NSUN3 Remodeling the Glioma Immune Microenvironment by Driving Tunneling Nanotube-Mediated Mitochondrial Transfer via tRNA Modification

Project description:Glioma is characterized by an immunosuppressive tumor microenvironment (TME) that promotes immune escape and therapeutic resistance. Mitochondrial transfer mediated by tunneling nanotubes (TNTs) is critical for tumor-stroma crosstalk, yet the underlying epigenetic regulatory mechanism remains unclear. Here, we report that the RNA m5C methyltransferase NSUN3 drives TNT formation and intercellular mitochondrial transfer in glioma by catalyzing m5C modification on tRNAs. Using tRNA-specific bisulfite sequencing (tRNA-BSseq) on human glioma cells, we systematically profiled tRNA m5C methylation landscapes in NSUN3-overexpressing and control groups. We identified NSUN3-dependent m5C sites on tRNAs that modulate translation efficiency of key factors involved in TNT assembly and mitochondrial transport. Functional assays demonstrated that NSUN3-mediated tRNA m5C modification enhances TNT formation, facilitates mitochondrial transfer from stromal cells to glioma cells, and remodels the immune microenvironment by suppressing anti-tumor immunity and promoting immunosuppressive cell infiltration. Our study reveals a novel epitranscriptomic mechanism linking tRNA m5C methylation to intercellular organelle transfer and immune regulation in glioma, providing potential targets for glioma immunotherapy.

2026-05-11 | GSE330028 | GEO

NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation

Project description:Mitochondrial gene expression uses a non-universal genetic code in mammals. Besides reading the conventional AUG codon, mitochondrial (mt-)tRNAMet mediates incorporation of methionine on AUA and AUU codons during translation initiation and on AUA codons during elongation. We show that the RNA methyltransferase NSUN3 localises to mitochondria and interacts with mt-tRNAMet to methylate cytosine 34 (C34) at the wobble position. NSUN3 specifically recognises the anticodon stem loop (ASL) of the tRNA, explaining why a mutation that compromises ASL basepairing leads to disease. We further identify ALKBH1/ABH1 as the dioxygenase responsible for oxidising m5C34 of mt-tRNAMet to generate an f5C34 modification. In vitro codon recognition studies with mitochondrial translation factors reveal preferential utilization of m5C34 mt-tRNAMet in initiation. Depletion of either NSUN3 or ABH1 strongly affects mitochondrial translation in human cells, implying that modifications generated by both enzymes are necessary for mt-tRNAMet function. Together, our data reveal how modifications in mt-tRNAMet are generated by the sequential action of NSUN3 and ABH1, allowing the single mitochondrial tRNAMet to recognise the different codons encoding methionine. HEK293 cell lines expressing His-FLAG-tagged NSUN3 or the His-FLAG tag alone were crosslinked using UV or treated with 5-azacytidine and analysed by CRAC

2016-08-09 | E-GEOD-84664 | biostudies-arrayexpress

Distinct NSun methylases control cytosine-5 methylation of messenger, mitochondrial and transfer RNA: implications for human diseases [miCLIP & Bisfulfite-Seq HEK293]

Project description:Aberrant post-transcriptional methylation is implicated in a wide range of human diseases, yet the specific enzymes responsible for site- and substrate-specific methylation remain largely unknown. Here, we use our recently developed catalysis-dependent RIP sequencing approach (miCLIP) and RNA bisulfite sequencing to map C5-methylcytosine (m5C) in the human transcriptome. We identified two novel m5C methylases NSun3 and NSun6, both of which have strong substrate specificity. In contrast to the previously characterized NSun2, which displays some preference to methylating transfer RNAs (tRNA), NSun6 predominantly targeted 3’ UTRs of messenger RNAs (mRNA), and NSun3 mainly methylated mitochondrial RNAs (mtRNA). Consistent with the miCLIP-predicted RNA target specificity, whole exome sequencing identified NSUN3 loss-of-function mutations in a patient presenting with combined respiratory chain complex deficiency. Functional studies of the patient fibroblast cell line revealed that loss of the NSun3 protein resulted in severe mitochondrial translation defects, which were rescued by expression of wild-type NSun3. In summary, our results reveal how highly conserved NSun m5C methylases partition their substrate specificities to remodel the sequences of particular ribonucleotide classes.

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NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation

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A cohort of mRNAs undergo high-stoichiometry NSUN6-mediated site-specific m5C modification

Project description:mRNA modifications are vital in regulating cellular processes. Beyond N6-methyladenosine (m6A), most other internal mRNA modifications lack dedicated catalytic machinery and are typically introduced by tRNA-modifying enzymes. The distribution and stoichiometry of these modifications on mRNAs remain debated and require further validation. Furthermore, their precise function remains controversial due to the challenges of excluding the intricate combinational effects of tRNA modifications. Here, we biochemically validate that NSUN6, a tRNA structure-dependent methyltransferase, independently catalyzes 5-methylcytidine (m5C) formation with robust activity on mRNA by recognizing the CUCCA motif in a certain stem-loop structure. NSUN6 employs different strategies to recognize tRNA and mRNA substrates. By introducing mutations, we further separate its catalytic capabilities toward mRNA and tRNA revealing that NSUN6 promotes breast cancer cell migration depending on mRNA m5C modification. Mechanistically, a cohort of mRNAs involved in cell migration carries high levels of NSUN6-mediated site-specific m5C modification, thus being stabilized by the preferential binding of m5C readers YBX1 and YBX3. Moreover, introducing a single-site high-level m5C can significantly increase the stability of therapeutic mRNAs in cells. Our findings underscore the pivotal role of m5C-modified mRNAs in promoting breast cancer metastasis and their potential for therapeutic applications.

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A cohort of mRNAs undergo high-stoichiometry NSUN6-mediated site-specific m5C modification to promote breast cancer metastasis

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m5C methyltransferase NSUN3 regulates variant gene expression and development in blood-stage Plasmodium falciparum [RIP-seq]

Project description:m5C methyltransferase NSUN3 regulates variant gene expression and development in blood-stage Plasmodium falciparum [RIP-seq]

| PRJNA1139780 | ENA

m5C methyltransferase NSUN3 regulates variant gene expression and development in blood-stage Plasmodium falciparum [RNA-seq]

Project description:m5C methyltransferase NSUN3 regulates variant gene expression and development in blood-stage Plasmodium falciparum [RNA-seq]

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RNA-seq profiles of Arabidopsis thaliana wild-type and trm4b-4

Project description:Methylation of carbon 5 in cytosine (5-methylcytosine; m5C) is a well-characterized DNA modification, and is also predominantly reported in highly abundant noncoding RNAs, such as rRNA and tRNA, in both prokaryotes and eukaryotes. However, the distribution and biological functions of m5C in plant mRNAs remain largely unknown. Here we develop an m5C RNA immunoprecipitation followed by deep sequencing approach (m5C-RIP-seq) to achieve transcriptome-wide profiling of RNA m5C in Arabidopsis thaliana. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and dot blot analyses reveal a dynamic pattern of m5C mRNA modification in various tissues and at different developmental stages. m5C-RIP-seq analysis identifies 6,045 putative m5C peaks in 4,465 expressed genes in young seedlings. m5C is enriched in coding sequences with two peaks located immediately after start codons and before stop codons, and is associated with mRNAs with low translation activity. We further show that a RNA (cytosine-5)-methyltransferase, tRNA specific methyltransferase 4B (TRM4B), exhibits the m5C mRNA methyltransferase activity. Mutations in TRM4B display defects in root development and decreased m5C levels in root mRNA. Furthermore, TRM4B affects transcript levels of the genes involved in root development, which is positively correlated with their mRNA stability and m5C levels. Our results suggest that m5C in mRNA is a new epitranscriptome marker widely distributed in plant genes, and that regulation of this modification is an integral part of gene regulatory networks underlying plant development.

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