NSUN2-mediated 5-methylcytosine enhances purine metabolism through ALYREF in retinoblastoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE214685 | GEO | 2022/10/07
REPOSITORIES: GEO
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Project description:NSUN2-mediated 5-methylcytosine enhances purine metabolism through ALYREF in retinoblastoma
| PRJNA886684 | ENA
Project description:5-methylcytosine (m5C) modification ubiquitously occurs on mammalian mRNAs and plays important roles in multiple biological processes. Currently, the role of m5C in cancer initiation and progression is gaining more and more research attention, but the detailed mechanism remains unclear. As an m5C methyltransferase with unique mRNA catalytic activity, NSUN2 was found to be highly expressed in multiple cancers including gastric, bladder, gallbladder, and breast cancers, suggesting NSUN2 might exert oncogenic properties through affecting m5C levels in cancer cells. Therefore, to understand the potential roles of RNA m5C modification in tumorigenesis of cervical cancer, we established NSUN2 stable knockdown CaSki cell, and perform RNA-seq and RNA-BisSeq to figure out the possible pathway involved in cervical cancer development.
2021-09-24 | GSE184621 | GEO
Project description:Purpose: The precise temporal and spatial regulation of N5-methylcytosine (m5C) RNA modification plays essential roles in RNA metabolism. Targeting m5C regulation in cancer cells may be a potential strategy for cancer therapy. Erianin is a natural product isolated from Dendrobium chrysotoxum Lindl. Howbeit, the in‐depth understanding of interaction between erianin and m5C modification remains indistinct. Methods: Natural product library screening was used to explore the effects of natural product monomers on uveal melanoma (UM) cells. Intraocular xenografts model was established to examine the effect of erianin. Immunoprecipitation mass spectrometry (IP-MS) and molecular docking analyses were performed to identify NSUN2 as the target of erianin. m5C-meRIP-seq and m5C-meRIP-qPCR analyses were performed to identify the functional target of NSUN2. Tube formation assay and CD31-PAS double staining were used to detect vasculogenic mimicry (VM) in UM. Results: Herein, we report the discovery of erianin as an effective inhibitor of uveal melanoma. Mechanistically, the targeted inhibition of NSUN2 function by erianin results in a decrease in the m5C modification and expression levels of CHAC1 in UM, thereby curtailing the formation of VM. Conclusions: Collectively, our data suggested that erianin significantly inhibited UM progression in vitro and in vivo. Our study unveils a novel therapeutic strategy for combating UM.
2024-12-10 | GSE280936 | GEO
Project description:Background: As a widespread post-transcriptional RNA modification, N5-methylcytosine (m5C) is implicated in a variety of cellular responses and processes that regulate RNA metabolism. Despite this, a clear understanding of m5C modification’s role and mechanism in angiogenesis is still lacking. Methods: Single-cell RNA sequencing data was analyzed to determine expression of m5C methylase NSUN2. m5C levels were determined by mRNA isolation and anti-m5C dot blot in both hypoxia-induced endothelial cells (ECs) and laser-induced choroidal neovascularization (CNV). In addition, endothelial cell and endothelium‐specific NSUN2‐knockout mouse model were used to investigate the effect of NSUN2 silence on angiogenic phenotype. Genome-wide multiomics analyses were performed to identify the functional target of NSUN2, including proteomic analysis, transcriptome screening and m5C-methylated RNA immunoprecipitation sequencing (m5C-meRIP-seq). CUT&Tag sequencing was performed to test the histone lactylation signal in the promoter region of NSUN2. Finally, AAV-mediated short hairpin RNAi knockdown of NSUN2 gene expression (AAV-shNSUN2) was constructed to investigate the effect of inhibiting CNV. Results: First, we discovered that m5C methylase NSUN2 expression level and mRNA m5C level were significantly higher in CNV-ECs than in normal ECs. NSUN2 knockdown in ECs inhibited proliferative, migration, and tube formation activities of ECs. Moreover, compared with EC NSUN2flox/flox mice, EC-specific NSUN2-deficient (EC NSUN2-/-) mice displayed less retinal vascular leakage after laser induction. Through multiomics analyses, we subsequently identified A-kinase anchoring protein 2 (AKAP2), a scaffolding protein which isolate Protein kinase A (PKA) to specific subcellular locations through binding to its regulatory subunit, as a downstream candidate target of NSUN2 in ECs. Overexpression of exogenous AKAP2 markedly reversed the inhibitory phenotypes in NSUN2-deficient ECs. Interestingly, laser induced NSUN2 up-regulation was driven by lactate-mediated lactylation on histone H3K18. In CNV models, AAV-mediated repression of NSUN2 modulated highly retinal vascular leakage and choroidal thickness. Conclusion: Overall, our findings indicate that NSUN2 is a novel therapeutic target for choroidal neovascularization.
2024-05-19 | GSE267661 | GEO
Project description:Background: As a widespread post-transcriptional RNA modification, N5-methylcytosine (m5C) is implicated in a variety of cellular responses and processes that regulate RNA metabolism. Despite this, a clear understanding of m5C modification’s role and mechanism in angiogenesis is still lacking. Methods: Single-cell RNA sequencing data was analyzed to determine expression of m5C methylase NSUN2. m5C levels were determined by mRNA isolation and anti-m5C dot blot in both hypoxia-induced endothelial cells (ECs) and laser-induced choroidal neovascularization (CNV). In addition, endothelial cell and endothelium‐specific NSUN2‐knockout mouse model were used to investigate the effect of NSUN2 silence on angiogenic phenotype. Genome-wide multiomics analyses were performed to identify the functional target of NSUN2, including proteomic analysis, transcriptome screening and m5C-methylated RNA immunoprecipitation sequencing (m5C-meRIP-seq). CUT&Tag sequencing was performed to test the histone lactylation signal in the promoter region of NSUN2. Finally, AAV-mediated short hairpin RNAi knockdown of NSUN2 gene expression (AAV-shNSUN2) was constructed to investigate the effect of inhibiting CNV. Results: First, we discovered that m5C methylase NSUN2 expression level and mRNA m5C level were significantly higher in CNV-ECs than in normal ECs. NSUN2 knockdown in ECs inhibited proliferative, migration, and tube formation activities of ECs. Moreover, compared with EC NSUN2flox/flox mice, EC-specific NSUN2-deficient (EC NSUN2-/-) mice displayed less retinal vascular leakage after laser induction. Through multiomics analyses, we subsequently identified A-kinase anchoring protein 2 (AKAP2), a scaffolding protein which isolate Protein kinase A (PKA) to specific subcellular locations through binding to its regulatory subunit, as a downstream candidate target of NSUN2 in ECs. Overexpression of exogenous AKAP2 markedly reversed the inhibitory phenotypes in NSUN2-deficient ECs. Interestingly, laser induced NSUN2 up-regulation was driven by lactate-mediated lactylation on histone H3K18. In CNV models, AAV-mediated repression of NSUN2 modulated highly retinal vascular leakage and choroidal thickness. Conclusion: Overall, our findings indicate that NSUN2 is a novel therapeutic target for choroidal neovascularization.
2024-05-19 | GSE267662 | GEO
Project description:Background: Colorectal cancer (CRC) is a harmful cancer with high morbidity and poor prognosis. There is growing evidence that RNA methylation is closely related to the occurrence of cancer and its malignant biological behavior. N6-methyladenosine (m6A) methylation is the most common RNA modification in eukaryotes, and its multiple regulatory mechanisms in CRC have been elucidated from multiple perspectives. At the same time, the role of 5-methylcytosine (m5C), another important and widely distributed methylation modification, in CRC is far from being elucidated. Methods: In this study, we used RNA immunoprecipitation sequencing combined with bioinformatics methods to identify the m5C peaks on messenger RNA (mRNA) in HCT15 cells and sh-NSUN2 HCT15 cells, understand which transcripts are modified by m5C, and characterize the distribution of m5C modifications. In addition, we performed further bioinformatics analysis of the detected data to initially clarify the potential function of these m5C-modified transcripts. Results: We found significant differences in the distribution of m5C between HCT15 cells and sh-NSUN2 HCT15 cells, suggesting that m5C is likely to play a key role in the occurrence and development of CRC. Furthermore, Gene Ontology (GO) enrichment analysis showed that genes altered by m5C were mainly enriched in phylogeny, synaptic membrane, and transcription factor binding.The Kyoto Encyclopedia of Genes and Genomes（KEGG）pathway analysis showed that the genes altered by m5C are enriched in ECM receptor interaction pathway, the circadian pathway, and the cAMP signaling pathway. Conclusions: Here, our study preliminarily revealed the different distribution patterns of m5C between HCT15 cell and sh-NSUN2 HCT15 cell. Our results open a new window to understand the role of m5C RNA methylation of mRNA in the development of CRC.
2023-03-02 | GSE226129 | GEO
Project description:5-methylcytosine (m5C) is emerging as an important epi-transcriptome modification involving RNA stability and translation efficiency in various biological processes. However, it remains unclear how m5C contributes to the dynamic regulation of transcriptome during the development of Plasmodium. Here, we identified the presence of 5-methylcytosine (m5C) modification in rodent (P. yoelii) and human (P. falciparum) malaria parasites transcriptome and depicted a comprehensive characterization landscape of m5C mRNA modification at single-nucleotide resolution (RNA-BisSeq) from asexual replicating stage to gametocyte development. Through transcriptome-wide profiling of mRNA m5C modification, we found that m5C modified mRNA displayed higher stability than non-m5C modified mRNA during the development of Plasmodium. We identified Plasmodium ortholog of NSUN2 as an mRNA m5C methyltransferase in malaria parasites. LC–MS/MS and RNA-BisSeq analysis revealed a large decrease in mRNA m5C modification at transcriptome-wide level upon Nsun2 knockout. Absence of Nsun2 severely reduced gametocyte production in either rodent (P. yoelii) or human (P. falciparum) malaria parasites. Meanwhile, some genes related to gametocytogenesis displayed a great reduction of m5C modification. Together, our data provides comprehensive mRNA m5C profiles in Plasmodium genus and reveals m5C modification-mediated mRNA stability as a novel mechanism regulating sexual differentiation of a unicellular eukaryote.
2022-02-08 | GSE159125 | GEO
Project description:5-methylcytosine (m5C) is emerging as an important epi-transcriptome modification involving RNA stability and translation efficiency in various biological processes. However, it remains unclear how m5C contributes to the dynamic regulation of transcriptome during the development of Plasmodium. Here, we identified the presence of 5-methylcytosine (m5C) modification in rodent (P. yoelii) and human (P. falciparum) malaria parasites transcriptome and depicted a comprehensive characterization landscape of m5C mRNA modification at single-nucleotide resolution (RNA-BisSeq) from asexual replicating stage to gametocyte development. Through transcriptome-wide profiling of mRNA m5C modification, we found that m5C modified mRNA displayed higher stability than non-m5C modified mRNA during the development of Plasmodium. We identified Plasmodium ortholog of NSUN2 as an mRNA m5C methyltransferase in malaria parasites. LC–MS/MS and RNA-BisSeq analysis revealed a large decrease in mRNA m5C modification at transcriptome-wide level upon Nsun2 knockout. Absence of Nsun2 severely reduced gametocyte production in either rodent (P. yoelii) or human (P. falciparum) malaria parasites. Meanwhile, some genes related to gametocytogenesis displayed a great reduction of m5C modification. Together, our data provides comprehensive mRNA m5C profiles in Plasmodium genus and reveals m5C modification-mediated mRNA stability as a novel mechanism regulating sexual differentiation of a unicellular eukaryote.
2022-02-08 | GSE159126 | GEO
Project description:5-methylcytosine (m5C) is emerging as an important epi-transcriptome modification involving RNA stability and translation efficiency in various biological processes. However, it remains unclear how m5C contributes to the dynamic regulation of transcriptome during the development of Plasmodium. Here, we identified the presence of 5-methylcytosine (m5C) modification in rodent (P. yoelii) and human (P. falciparum) malaria parasites transcriptome and depicted a comprehensive characterization landscape of m5C mRNA modification at single-nucleotide resolution (RNA-BisSeq) from asexual replicating stage to gametocyte development. Through transcriptome-wide profiling of mRNA m5C modification, we found that m5C modified mRNA displayed higher stability than non-m5C modified mRNA during the development of Plasmodium. We identified Plasmodium ortholog of NSUN2 as an mRNA m5C methyltransferase in malaria parasites. LC–MS/MS and RNA-BisSeq analysis revealed a large decrease in mRNA m5C modification at transcriptome-wide level upon Nsun2 knockout. Absence of Nsun2 severely reduced gametocyte production in either rodent (P. yoelii) or human (P. falciparum) malaria parasites. Meanwhile, some genes related to gametocytogenesis displayed a great reduction of m5C modification. Together, our data provides comprehensive mRNA m5C profiles in Plasmodium genus and reveals m5C modification-mediated mRNA stability as a novel mechanism regulating sexual differentiation of a unicellular eukaryote.
2022-02-08 | GSE159124 | GEO
Project description:The 5-methylcytosine (m5C) modification is present at appreciable amounts in the mammalian transcriptome, but its precise location and function is still poorly understood. Here, we identify high m5C levels and map their locations in a model retrovirus, the murine leukemia virus, and show that the ALYREF m5C reader protein regulates viral replication. Our results reveal a single-nucleotide m5C profile in a virus and its function in a eukaryotic mRNA.
2020-04-14 | GSE139606 | GEO