NSUN2 mediated m5C modification regulates myocardial hypertrophy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA981449 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR24874632.fastq.gz | Fastqsanger.gz | |||
| SRR24874632_1.fastq.gz | Fastqsanger.gz | |||
| SRR24874632_2.fastq.gz | Fastqsanger.gz | |||
| SRR24874633.fastq.gz | Fastqsanger.gz |
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Project description:Aims: Mammalian mRNA internal modification m6A has been suggested to be essential in the maintenance of cardiac homeostasis. The role of mRNA cytosine methylation (m5C) in the heart remains unexplored.Methods and results: In contrast with human normal heart, the expression of RNA cytosine methyltransferase NSun2 was found to be significantly elevated in the hypertrophied one. Consistently, NSun2 expression was increased in hypertrophic rat ventricular myocytes induced in vitro, as well as in TAC (transverse aortic constriction) developed hypertrophied murine heart. Cardiomyocyte-specific knockout of NSun2 (Myh6-CreERT2, NSun2 flox+/+) dramatically accelerated heart failure progression in TAC mice. RNA m5C immunoprecipitation followed by sequencing and MeRIP (methylation-specific RNA immunoprecipitation) revealed that NSun2 particularly methylates the mRNA of protein kinase A (PKA) catalytic subunit alpha (PRKACA). Polyribosome and dual luciferase reporter gene analysis further suggested that NSun2 promotes PRKACA translation via RNA methylation. In TAC hypertrophic cardiomyocytes, NSun2 ablation markedly dampened PKA signaling, as evidenced by reduced PKA activity and protein phosphorylation levels of PKA diverse substrates, impaired myocyte contraction and relaxation, and disturbed calcium transients. Cardiac-restricted overexpression of NSun2 via adeno-associated virus 9 (AAV9, NSun2 expression cassette driven by cTnT promoter) sensitized heart hypertrophic response, whereas administration of PKA inhibitor H89 successfully blocked this process, reiterating the importance of NSun2-PRKACA regulation in cardiac hypertrophic program.Conclusions: Our study showed that RNA methyltransferase NSun2 promotes PRKACA translation via RNA methylation, whereby achieving its modulation of PKA signaling within the cardiomyocyte. NSun2-PRKACA regulation is required for cardiac homeostasis maintenance and adaptation to hypertrophic stresses. These findings furnish us with novel understanding of heart function mediated by mRNA cytosine methylation in cardiac homeostasis.
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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.
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Project description:Lactylation, a metabolic stress-induced modification, plays a pivotal role in regulating diverse biological processes. Its involvement in perineural invasion (PNI) of pancreatic ductal adenocarcinoma (PDAC), however, has not been clearly defined. Our study demonstrates that patients with severe PNI exhibit significantly elevated levels of global lactylation and lactate, correlating with poorer prognosis. We identified NSUN2, a methyltransferase, as a crucial mediator of lactylation-driven PNI. Inhibition of lactylation or NSUN2 markedly reduced the neural infiltration capabilities of tumor cells. Mechanistically, lactate accumulation leads to the lactylation of NSUN2 at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of NSUN2 mediated m5C modification on CDCP1 and STC11 mRNA, enhanced their mRNA stability. Consistently, analyses using a KPC mouse model demonstrated that the lactylation of NSUN2/CDCP1/STC11 axis enhanced PNI through m5C modification. Our findings reveal that lactylation-driven NSUN2-mediated RNA m5C modification plays a pivotal role in promoting PNI and suggest that targeting NSUN2 could offer a promising therapeutic strategy for PDAC.
2025-06-15 | GSE299600 | GEO
Project description:Lactylation, a metabolic stress-induced modification, plays a pivotal role in regulating diverse biological processes. Its involvement in perineural invasion (PNI) of pancreatic ductal adenocarcinoma (PDAC), however, has not been clearly defined. Our study demonstrates that patients with severe PNI exhibit significantly elevated levels of global lactylation and lactate, correlating with poorer prognosis. We identified NSUN2, a methyltransferase, as a crucial mediator of lactylation-driven PNI. Inhibition of lactylation or NSUN2 markedly reduced the neural infiltration capabilities of tumor cells. Mechanistically, lactate accumulation leads to the lactylation of NSUN2 at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of NSUN2 mediated m5C modification on CDCP1 and STC11 mRNA, enhanced their mRNA stability. Consistently, analyses using a KPC mouse model demonstrated that the lactylation of NSUN2/CDCP1/STC11 axis enhanced PNI through m5C modification. Our findings reveal that lactylation-driven NSUN2-mediated RNA m5C modification plays a pivotal role in promoting PNI and suggest that targeting NSUN2 could offer a promising therapeutic strategy for PDAC.
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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.
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Project description:RNA expression and m5c modification in NSUN2 kncok down CaSki cell
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Project description:Herpesviruses are a group of double-stranded DNA viruses known to develop versatile viral strategies to escape host immune surveillance for promoting their replication and propagation. This is illustrated by Kaposi’s sarcoma-associated herpesvirus (KSHV), an oncogenic gamma-herpesvirus that overcomes host immune suppression by multiple mechanisms. In this study, we reported that KSHV dysregulates 5-methylcytosine (m5C) modification and mRNA stability of host antiviral factors to benefit its lytic replication. KSHV lytic reactivation or de novo challenge led to downregulation of m5C RNA methyltransferases, NSUN2 and NSUN1 (NSUN2/1), while NSUN2/1 depletion promoted KSHV lytic replication. We further performed the RNA bisulfite sequencing (RNA-BS-seq) to identify KSHV-dependent m5C modification of host mRNAs. Overall, our results highlighted a new strategy for human gamma-herpesviruses to counteract host antiviral factors and promote their lytic replication by manipulating host m5C RNA methylation.
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Project description:5-methylcytosine (m5C) RNA modification installed by methyltransferase NSUN2 regulates gene expression and cell fate. Retinoblastoma (RB) is the most common primary intraocular tumor in children. However, the functional role of m5C modification in retinoblastoma remains unclear. Here, we show that 5-methylcytosine significantly promotes the progression of retinoblastoma. Retinoblastoma samples showed increased m5C levels, indicating a poor prognosis. Changes in global m5C modification were highly associated with tumor progression in vitro and in vivo. Mechanistically, NSUN2 stabilized the methylated PFAS mRNA, a tumor promoter in retinoblastoma. Our work uncovers a critical function for m5C methylation in retinoblastoma and provides additional insight into the understanding of m5C modification.
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Project description:5-methylcytosine, an abundant RNA modification, plays a crucial role in regulating RNA fate and gene expression. While recent progress has been made in understanding the biological roles of m5C, the inability to introduce m5C at specific sites within transcripts has hindered efforts to elucidate direct links between specific m5C and phenotypic outcomes. Here we developed a CRISPR-Cas13d-based tool, named reengineered m5C modification systems (termed ‘RCMS’), for targeted m5C methylation and demethylation in specific transcripts. The RCMS editors consist of a nuclear-localised dCasRx conjugated to either to a methyltransferase, NSUN2/NSUN6 or a demethylase, the catalytic domain of mouse Tet2 (Tet2 CD), enabling the manipulation of methylation events at precise m5C sites. We demonstrate that the RCMS editors can direct site-specific m5C incorporation and demethylation. Furthermore, we confirm their effectiveness in modulating m5C levels within tRNAs and their ability to induce changes in transcript abundance and cell proliferation through m5C-mediated mechanisms. These findings collectively establish RCMS editors as a focused epitranscriptome engineering tool, facilitating the identification of individual m5C alterations and their consequential effects.
2025-01-19 | GSE253659 | 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