RESUMEN
Cancer remains a leading cause of morbidity and mortality worldwide, necessitating the ongoing investigation of molecular targets for improved diagnosis, prognosis, and therapy. Among these targets, RNA modifications, particularly N5-methylcytosine (m5C) in RNA, have emerged as critical regulators of gene expression and cellular functions. NOP2/Sun RNA methyltransferase family member 2 (NSUN2) is a key enzyme in m5C modification, significantly influencing various biological processes and tumorigenesis. NSUN2 methylates multiple RNA species, including transfer RNAs (tRNAs), messenger RNAs (mRNAs), and non-coding RNAs, impacting RNA stability, translation efficiency, and cellular stress responses. These modifications, in turn, affect cell proliferation, differentiation, and survival. In cancer, NSUN2 is frequently upregulated, associated with aggressive tumor phenotypes, poor prognosis, and therapy resistance. Its role in oncogenic signaling pathways further underscores its importance in cancer biology. This review offers a comprehensive overview of NSUN2's role in cancer, focusing on its involvement in RNA methylation and its implications for tumor initiation and progression. Additionally, we explore the potential of NSUN2 as a biomarker for cancer diagnosis and prognosis, and its promise as a therapeutic target.
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Metiltransferasas , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Metiltransferasas/metabolismo , Metilación , ARN/metabolismo , Animales , Regulación Neoplásica de la Expresión Génica , Relevancia Clínica , Metilación de ARNRESUMEN
Extracellular vesicles secreted by bone marrow mesenchymal stem cells (BM-MSCs) exert therapeutic effects in osteoarthritis (OA). As an important N6-Methyladenosine (m6A) demethylase, it is reported that fat mass and obesity-associated protein (FTO) involves in regulating OA progression. Here, we generated MSCs-derived FTO-overexpressing EVs (FTO-EVs) to investigate whether FTO-EVs could be used for the potential treatment of OA. Our experiments verify that FTO-EVs suppressed cellular senescence, aging, apoptosis, and enhanced cell autophagy in LPS-treated chondrocytes in vitro and monosodium iodoacetate (MIA)-treated mice tissues in vivo. Also, ROS scavenger NAC reversed LPS-induced detrimental effects in chondrocytes. Mechanical experiments illustrated that FTO-EVs induced m6A-demethylation in autophagy-associated genes (Atg5 and Atg7) and pro-apoptosis gene (BNIP3), subsequently inducing the upregulation of Atg5/Atg7 and downregulation of BNIP3 in a YTHDF2-dependent manner, and the effects of FTO-EVs on the expressions of Atg5/Atg7 and BNIP3 were all reversed by upregulating m6A methyltransferase METTL3. Furthermore, FTO-EVs-induced suppressing effects on LPS-treated chondrocytes senescence and aging were abolished by Atg5/Atg7 knockdown and BNIP3 overexpression. In conclusion, this study evidenced that BM-MSCs-derived FTO-EVs suppressed cellular senescence and apoptosis, and triggered protective autophagy to suppress OA development through demethylating m6A modifications, and the engineering FTO-EVs could be potentially used to treat OA in clinic.
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Senescencia Celular , Condrocitos , Vesículas Extracelulares , Células Madre Mesenquimatosas , Metiltransferasas , Osteoartritis , Proteínas de Unión al ARN , Animales , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Vesículas Extracelulares/metabolismo , Osteoartritis/metabolismo , Osteoartritis/terapia , Osteoartritis/patología , Osteoartritis/genética , Ratones , Células Madre Mesenquimatosas/metabolismo , Metiltransferasas/metabolismo , Metiltransferasas/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Condrocitos/metabolismo , Autofagia , Adenosina/análogos & derivados , Adenosina/metabolismo , Apoptosis , Envejecimiento/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , ARN/metabolismo , ARN/genética , Metilación de ARN , Proteínas MitocondrialesRESUMEN
BACKGROUND: Social isolation not only increases the risk of mortality in later life but also causes depressive symptoms, cognitive and physical disabilities. Although RNA m6A modifications are suggested to play key roles in brain development, neuronal signaling and neurological disorders, both the roles of m6A and the enzymes that regulate RNA m6A modification in social isolation induced abnormal behavior is unknown. The present study aims to explore the possible epitranscriptomic role of RNA m6A modifications and its enzymes in social isolation induced impaired behavior. METHODS: 3-4 weeks mice experiencing 8 weeks social isolation stress (SI) were used in the present study. We quantified m6A levels in brain regions related to mood and cognitive behavior. And the expression of hippocampal m6A enzymes was also determined. The role of hippocampal m6A and its enzymes in SI induced abnormal behavior was further verified by the virus tool. RESULTS: SI led to not only depressive and anxiety-like behaviors but also cognitive impairment, with corresponding decreases in hippocampal m6A and METTL14. Hippocampal over-expression METTL14 with lentivirus not only rescued these behaviors but also enhanced the hippocampal m6A level. Hippocampal over-expression METTL14 resulted in increased synaptic related genes. CONCLUSIONS: We provide the first evidence that post-weaning social isolation reduces hippocampal m6A level and causes altered expression of m6A enzyme in mice. Importantly, hippocampal METTL14 over-expression alleviated the SI-induced depression/anxiety-like and impaired cognitive behaviors and enhanced m6A level and synaptic related genes expression.
Asunto(s)
Hipocampo , Metiltransferasas , Aislamiento Social , Animales , Hipocampo/metabolismo , Masculino , Ratones , Metiltransferasas/genética , Metiltransferasas/metabolismo , Depresión/genética , Depresión/metabolismo , Conducta Animal/fisiología , Ansiedad/genética , Ansiedad/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/genética , Ratones Endogámicos C57BL , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Epigénesis Genética , Metilación de ARNRESUMEN
BACKGROUND: Tumor recurrence and mortality rates remain challenging in cancer patients despite comprehensive treatment. Neoadjuvant chemotherapy and immunotherapy aim to eliminate residual tumor cells, reducing the risk of recurrence. However, drug resistance during neoadjuvant therapy is a significant hurdle. Recent studies suggest a correlation between RNA methylation regulators (RMRs) and response to neoadjuvant therapy. METHODS: Using a multi-center approach, we integrated advanced techniques such as single-cell transcriptomics, whole-genome sequencing, RNA sequencing, proteomics, machine learning, and in vivo/in vitro experiments. Analyzing pan-cancer cohorts, the association between neoadjuvant chemotherapy/immunotherapy effectiveness and RNA methylation using single-cell sequencing was investigated. Multi-omics analysis and machine learning algorithms identified genomic variations, transcriptional dysregulation, and prognostic relevance of RMRs, revealing distinct molecular subtypes guiding pan-cancer neoadjuvant therapy stratification. RESULTS: Our analysis unveiled a strong link between neoadjuvant therapy efficacy and RNA methylation dynamics, supported by pan-cancer single-cell sequencing data. Integration of omics data and machine learning algorithms identified RMR genomic variations, transcriptional dysregulation, and prognostic implications in pan-cancer. High-RMR-expressing tumors displayed increased genomic alterations, an immunosuppressive microenvironment, poorer prognosis, and resistance to neoadjuvant therapy. Molecular investigations and in vivo/in vitro experiments have substantiated that the JAK inhibitor TG-101,209 exerts notable effects on the immune microenvironment of tumors, rendering high-RMR-expressing pan-cancer tumors, particularly in pancreatic cancer, more susceptible to chemotherapy and immunotherapy. CONCLUSIONS: This study emphasizes the pivotal role of RMRs in pan-cancer neoadjuvant therapy, serving as predictive biomarkers for monitoring the tumor microenvironment, patient prognosis, and therapeutic response. Distinct molecular subtypes of RMRs aid individualized stratification in neoadjuvant therapy. Combining TG-101,209 adjuvant therapy presents a promising strategy to enhance the sensitivity of high-RMR-expressing tumors to chemotherapy and immunotherapy. However, further validation studies are necessary to fully understand the clinical utility of RNA methylation regulators and their impact on patient outcomes.
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Terapia Neoadyuvante , Neoplasias , Humanos , Terapia Neoadyuvante/métodos , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Resistencia a Antineoplásicos/genética , Animales , Ratones , Pronóstico , Microambiente Tumoral , Metilación de ARNRESUMEN
INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system. RNA methylation plays an important role in tumorigenesis and metastasis, which could alter gene expression and even function at multiple levels, such as RNA splicing, stability, translocation, and translation. In this study, we aimed to conduct a comprehensive analysis of RNA methylation-related genes (RMGs) in HCC and their relationship with survival and clinical features. METHODS: A retrospective analysis was performed using publicly available HCC-related datasets. The differentially expressed genes (DEGs) between HCC and controls were identified from TCGA-LlHC and intersected with RMGs to obtain differentially expressed RNA methylation-related genes (DERMGs). Regression analysis was used to screen for prognostic genes and construct risk models. Simultaneously, clinical, immune infiltration and therapeutic efficacy analyses were performed. Finally, multivariate cox regression was used to identify independent risk factors, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the expression levels of the core genes of the model. RESULTS: A 21-gene risk model for HCC was established with excellent performance based on ROC curves and survival analysis. Risk scores correlated with tumor grade, pathologic T, and TNM stage. Immune infiltration analysis showed correlations with immune scores, 11 immune cells, and 30 immune checkpoints. Low-risk patients showed a higher susceptibility to immunotherapy. The risk score and TNM stage were independent prognostic factors. qRT-PCR confirmed higher expression of PRDM9, ALPP, and GAD1 in HCC. CONCLUSIONS: This study identified RNA methylation-related signature genes in HCC and constructed a risk model that predicts patient outcomes and reflects the immune microenvironment. Prognostic genes are involved in complex regulatory mechanisms, which may be useful for cancer diagnosis, prognosis, and therapy.
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Biomarcadores de Tumor , Carcinoma Hepatocelular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/mortalidad , Microambiente Tumoral/genética , Pronóstico , Biomarcadores de Tumor/genética , Femenino , Masculino , Perfilación de la Expresión Génica , Transcriptoma , Biología Computacional/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Curva ROC , Estimación de Kaplan-Meier , Metilación de ADN , Metilación , Metilación de ARNRESUMEN
Even though N6-methyladenosine (m6A) RNA modifications are increasingly being implicated in human disease, their mechanisms are not fully understood in smokers with coronary artery disease (CAD). Thirty m6A-related regulators' expression (MRRE) in CAD individuals (smokers and non-smokers) were analyzed from GEO. Support Vector Machine, random forest, and nomogram models were constructed to assess its clinical value. Consensus clustering, principal component analysis, and ssGSEA were used to construct a full picture of m6A-related regulators in smokers with CAD. Oxygen-glucose deprivation (OGD) and qRT-PCR were used to validate hypoxia's effect on MRRE. A comparison between smokers with CAD and controls revealed lower expression levels of RBM15B, YTHDC2, and ZC3H13. Based on three key MRREs, all models showed good clinical value, and smokers with CAD were divided into two distinct molecular subgroups. The correlations were found between key MRRE and the degree of immune infiltration. Three key MRREs in HUVECs and FMC84 mouse cardiomyocytes were reduced in the OGD group. Through hypoxia, smoking might reduce the expression levels of RBM15B, YTHDC2, and ZC3H13 in smokers with CAD. Our findings provide an important theoretical basis for the treatment of smokers with CAD.
Asunto(s)
Adenosina , Enfermedad de la Arteria Coronaria , Proteínas de Unión al ARN , Humanos , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Ratones , Animales , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Fumar/efectos adversos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Masculino , Metilación de ARN , ARN HelicasasRESUMEN
BACKGROUND: N6-methyladenosine (m6A) has been identified as the most abundant modification of RNA molecules and the aberrant m6A modifications have been associated with the development of autoimmune diseases. However, the role of m6A modification in ankylosing spondylitis (AS) has not been adequately investigated. Therefore, we aimed to explore the significance of m6A regulator-mediated RNA methylation in AS. METHODS: The methylated RNA immunoprecipitation sequencing (meRIP-seq) and digital RNA sequencing (Digital RNA-seq) were conducted using the peripheral blood mononuclear cells from three AS cases and three healthy controls, to identify genes affected by abnormal RNA methylation. The genes associated with different peaks were cross-referenced with AS-related genes obtained from the GeneCards Suite. Subsequently, the expression levels of shared differentially expressed genes (DEGs) and key m6A regulators in AS were evaluated using data from 68 AS cases and 36 healthy controls from two data sets (GSE25101 and GSE73754). In addition, the results were validated through quantitative polymerase chain reaction (qPCR). RESULTS: The meRIP-seq and Digital RNA-seq analyses identified 28 genes with upregulated m6A peaks but with downregulated expression, and 52 genes with downregulated m6A peaks but with upregulated expression. By intersecting the genes associated with different peaks with 2184 AS-related genes from the GeneCards Suite, we identified a total of five shared DEGs: BCL11B, KAT6B, IL1R1, TRIB1, and ALDH2. Through analysis of the data sets and qPCR, we found that BCL11B and IL1R1 were differentially expressed in AS. Moreover, two key m6A regulators, WTAP and heterogeneous nuclear ribonucleoprotein C, were identified. CONCLUSIONS: In conclusion, the current study revealed that m6A modification plays a crucial role in AS and might hence provide a new treatment strategy for AS disease.
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Adenosina , Metilación de ARN , Espondilitis Anquilosante , Femenino , Humanos , Masculino , Adenosina/análogos & derivados , Adenosina/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Leucocitos Mononucleares/metabolismo , ARN/genética , Espondilitis Anquilosante/genéticaRESUMEN
N6-methyladenosine (m6A) is the most abundant epitranscriptomic mark that regulates the fate of RNA molecules. Recent studies have revealed a bidirectional interaction between m6A modification and the circadian clock. However, the precise temporal dynamics of m6A global enrichment in the central circadian pacemaker have not been fully elucidated. Our study investigates the relationship between FTO demethylase and molecular clocks in primary cells of the suprachiasmatic nucleus (SCN). In addition, we examined the effects of lipopolysaccharide (LPS) on Fto expression and the role of FTO in LPS-induced reactive oxygen species (ROS) production in primary SCN cell culture. We observed circadian rhythmicity in the global m6A levels, which mirrored the rhythmic expression of the Fto demethylase. Silencing FTO using siRNA reduced the mesor of Per2 rhythmicity in SCN primary cells and extended the period of the PER2 rhythm in SCN primary cell cultures from PER2::LUC mice. When examining the immune response, we discovered that exposure to LPS upregulated global m6A levels while downregulating Fto expression in SCN primary cell cultures. Interestingly, we found a loss of circadian rhythmicity in Fto expression following LPS treatment, indicating that the decrease of FTO levels may contribute to m6A upregulation without directly regulating its circadian rhythm. To explore potential protective mechanisms against neurotoxic inflammation, we examined ROS production following LPS treatment in SCN primary cell cultures pretreated with FTO siRNA. We observed a time-dependent pattern of ROS induction, with significant peak at 32 h but not at 20 h after synchronization. Silencing the FTO demethylase abolished ROS induction following LPS exposure, supporting the hypothesis that FTO downregulation serves as a protective mechanism during LPS-induced neuroinflammation in SCN primary cell cultures.
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Adenosina , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Relojes Circadianos , Lipopolisacáridos , Núcleo Supraquiasmático , Animales , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Ratones , Relojes Circadianos/efectos de los fármacos , Relojes Circadianos/fisiología , Relojes Circadianos/genética , Lipopolisacáridos/farmacología , Enfermedades Neuroinflamatorias/metabolismo , Metilación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas Circadianas Period/metabolismo , Proteínas Circadianas Period/genética , Células Cultivadas , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , ARN/genética , ARN/metabolismo , Metilación de ARNRESUMEN
BACKGROUND: A newly identified type of cell death due to intracellular copper accumulation is known as cuproptosis and RNA methylation is a post-transcriptional modification mechanism, both of which perform vital roles in the immune microenvironment of colorectal cancer (CRC), but the link between the two needs more research. METHODS: TCGA database provided RNA-seq data and details clinically of CRC samples. Cuproptosis-related RNA methylation regulators (CRRMRs) were identified by correlation analysis. We screened 6 CRRMRs for prognostic model construction by employing LASSO-Cox regression analysis and calculated risk scores by CRRMRs (CuMS). GSE39582 and GSE38832 cohort were used as external validation sets. This research concentrated on the connection between the prognostic model and somatic mutation, anti-cancer drug sensitivity, immune infiltration, immune checkpoint expression. In addition, we investigated the differential expression of YTHDC2 in epithelial cell subpopulations by single-cell analysis with GSE166555, calculated cuproptosis scores and performed pathway enrichment. In vitro experiments were performed to explore the consequences of knockdown of YTHDC2 on CRC cell proliferation and migration, as well as changes in CRC cell viability in response to elesclomol after knockdown of YTHDC2. In vivo experiments, we constructed the cell line-derived xenograft model to further validate the results of the in vitro experiments. RESULTS: The prognosis of CRC can be predicted by CuMS, which GSE39582 and GSE38832 confirmed. Two CuMS groups showed different tumor mutation burden (TMB) and immune infiltration. CuMS was connected to emerging immune checkpoints CD47 and PVR, therefore, it can be clinically complementary to TMB and microsatellite instability (MSI) status. In single-cell analysis, a subpopulation of epithelial cells with high YTHDC2 expression had a high cuproptosis score. In vitro experiments, knocking down YTHDC2 promoted cell proliferation and migration in CRC, and weaken the inhibitory effect of elesclomol and elesclomol-Cu on cell viability, which in vivo experiments validated. CONCLUSION: We developed a prognostic model constructed by 6 CRRMRs to assess overall survival and immune microenvironment of CRC patients. YTHDC2 might regulate cuproptosis in multiple ways.
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Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Animales , Ratones , Regulación hacia Abajo , Proliferación Celular , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Microambiente Tumoral/inmunología , Pronóstico , Metilación , Movimiento Celular/genética , Ratones Desnudos , Femenino , Masculino , Metilación de ARN , ARN HelicasasRESUMEN
The imbalance of vascular endothelial cell homeostasis is the key mechanism for the progression of many vascular diseases. RNA modification, particularly N6-Methyladenosine (m6A), plays important function in numerous biological processes. Nevertheless, the regulatory function of m6A RNA methylation in endothelial dysfunction remains insufficiently characterized. In this study, we established that the m6A methyltransferase METTL3 is critical for regulating endothelial function. Functionally, depletion of METTL3 results in decreased endothelial cells proliferation, survival and inflammatory response. Conversely, overexpression of METTL3 elicited the opposite effects. Mechanistically, MeRIP-seq identified that METTL3 catalyzed m6A modification of TRAF1 mRNA and enhanced TRAF1 translation, thereby up-regulation of TRAF1 protein. Over-expression of TRAF1 successfully rescued the inhibition of proliferation and adhesion of endothelial cells due to METTL3 knockdown. Additionally, m6A methylation-mediated TRAF1 expression can be reversed by the demethylase ALKBH5. Knockdown of ALKBH5 upregulated the level of m6A and protein level of TRAF1, and also increased endothelial cells adhesion and inflammatory response. Collectively, our findings suggest that METTL3 regulates vascular endothelium homeostasis through TRAF1 m6A modification, suggesting that targeting the METTL3-m6A-TRAF1 axis may hold therapeutic potential for patients with vascular diseases.
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Adenosina , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana , Inflamación , Metiltransferasas , Factor 1 Asociado a Receptor de TNF , Metiltransferasas/metabolismo , Metiltransferasas/genética , Humanos , Metilación , Inflamación/metabolismo , Inflamación/genética , Inflamación/patología , Factor 1 Asociado a Receptor de TNF/metabolismo , Factor 1 Asociado a Receptor de TNF/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Metilación de ARNRESUMEN
Fibroblast-like synoviocytes (FLS) plays an important role in synovial inflammation and joint damage in rheumatoid arthritis (RA). As the most abundant mRNA modification, N6-methyladenosine (m6A) is involved in the development of various diseases; however, its role in RA remains to be defined. In this study, we reported the elevated expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in FLS and synovium from RA patients. Functionally, FTO knockdown or treatment with FB23-2, an inhibitor of the mRNA m6A demethylase FTO, inhibited the migration, invasion and inflammatory response of RA FLS, however, FTO-overexpressed RA FLS exhibited increased migration, invasion and inflammatory response. We further demonstrated that FTO promoted ADAMTS15 mRNA stability in an m6A-IGF2BP1 dependent manner. Notably, the severity of arthritis was significantly reduced in CIA mice with FB23-2 administration or CIA rats with intra-articular injection of FTO shRNA. Our results illustrate the contribution of FTO-mediated m6A modification to joint damage and inflammation in RA and suggest that FTO might be a potential therapeutic target in RA.
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Adenosina , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Artritis Reumatoide , Inflamación , Metilación de ARN , Animales , Humanos , Ratones , Ratas , Adenosina/análogos & derivados , Adenosina/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Experimental/genética , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Artritis Reumatoide/genética , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Sinoviocitos/metabolismo , Sinoviocitos/patologíaRESUMEN
The underlying mechanism of the aluminum (Al) on neurotoxicity remains unclear. We explored whether the impairment of hippocampal neurons induced by developmental Al exposure was associated with the m6A RNA modification in mice. In this study, the pregnant female mice were administered 4â¯mg/mL aluminum-lactate from gestational day (GD) 6 to postnatal day (PND) 21. On PND 21, 10 offsprings per group were euthanized by exsanguination from the abdominal aorta after deep anesthetization. The other offsprings which treated with aluminum-lactate on maternal generation were divided into two groups and given 0 (PND60a) and 4â¯mg/mL (PND60b) aluminum-lactate in their drinking water until PND 60. Significant neuronal injuries of hippocampus as well as a reduction in the m6A RNA modification and the expression of methylase were observed at PND 21 and PND 60a mice. The results indicated that Al-induced developmental neurotoxicity could persist into adulthood despite no sustained Al accumulation. m6A RNA modification had a crucial role in developmental neurotoxicity induced by Al. In addition, Al exposure during the embryonic to adult stages can cause more severe nerve damage and decline of m6A RNA modification. Collectively, these results suggest that the mechanism underlying Al-induced neurotoxicity appears to involve m6A RNA modification.
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Hipocampo , Neuronas , Metilación de ARN , Animales , Femenino , Ratones , Embarazo , Aluminio/toxicidad , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Hipocampo/patología , Metiltransferasas/genética , Metiltransferasas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/metabolismo , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/etiología , Efectos Tardíos de la Exposición PrenatalRESUMEN
Cardiomyopathy (CM) represents a heterogeneous group of diseases primarily affecting cardiac structure and function, with genetic and epigenetic dysregulation playing a pivotal role in its pathogenesis. Emerging evidence from the burgeoning field of epitranscriptomics has brought to light the significant impact of various RNA modifications, notably N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N1-methyladenosine (m1A), 2'-O-methylation (Nm), and 6,2'-O-dimethyladenosine (m6Am), on cardiomyocyte function and the broader processes of cardiac and vascular remodelling. These modifications have been shown to influence key pathological mechanisms including mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis, inflammation, immune response, and myocardial fibrosis. Importantly, aberrations in the RNA methylation machinery have been observed in human CM cases and animal models, highlighting the critical role of RNA methylating enzymes and their potential as therapeutic targets or biomarkers for CM. This review underscores the necessity for a deeper understanding of RNA methylation processes in the context of CM, to illuminate novel therapeutic avenues and diagnostic tools, thereby addressing a significant gap in the current management strategies for this complex disease.
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Cardiomiopatías , Epigénesis Genética , ARN , Humanos , Animales , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Cardiomiopatías/terapia , ARN/genética , ARN/metabolismo , Metilación , Metilación de ARNRESUMEN
N 6-Methyladenosine (m6A) is a prevalent and highly regulated RNA modification essential for RNA metabolism and normal brain function. It is particularly important in the hippocampus, where m6A is implicated in neurogenesis and learning. Although extensively studied, its presence in specific cell types remains poorly understood. We investigated m6A in the hippocampus at a single-cell resolution, revealing a comprehensive landscape of m6A modifications within individual cells. Through our analysis, we uncovered transcripts exhibiting a dense m6A profile, notably linked to neurological disorders such as Alzheimer's disease. Our findings suggest a pivotal role of m6A-containing transcripts, particularly in the context of CAMK2A neurons. Overall, this work provides new insights into the molecular mechanisms underlying hippocampal physiology and lays the foundation for future studies investigating the dynamic nature of m6A RNA methylation in the healthy and diseased brain.
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Adenosina , Hipocampo , Análisis de la Célula Individual , Hipocampo/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Animales , Análisis de la Célula Individual/métodos , Ratones , Neuronas/metabolismo , Procesamiento Postranscripcional del ARN , Metilación , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , ARN/metabolismo , ARN/genética , Humanos , Metilación de ARNRESUMEN
Exposure to fine particulate matter (PM2.5) is a significant risk factor for hepatic steatosis. The N6-methyladenosine (m6A) is implicated in metabolic disturbances triggered by exogenous environmental factors. However, the role of m6A in mediating PM2.5-induced hepatic steatosis remains unclear. Herein, male C57BL/6J mice were subjected to PM2.5 exposure throughout the entire heating season utilizing a real-ambient PM2.5 whole-body inhalation exposure system. Concurrently, HepG2 cell models exposed to PM2.5 were developed to delve the role of m6A methylation modification. Following PM2.5 exposure, significant hepatic lipid accumulation and elevated global m6A level were observed both in vitro and in vivo. The downregulation of YTHDC2, an m6A-binding protein, might contribute to this alteration. In vitro studies revealed that lipid-related genes CEPT1 and YWHAH might be targeted by m6A modification. YTHDC2 could bind to CDS region of them and increase their stability. Exposure to PM2.5 shortened mRNA lifespan and suppressed the expression of CEPT1 and YWHAH, which were reversed to baseline or higher level upon the enforced expression of YTHDC2. Consequently, our findings indicate that PM2.5 induces elevated m6A methylation modification of CEPT1 and YWHAH by downregulating YTHDC2, which in turn mediates the decrease in the mRNA stabilization and expression of these genes, ultimately resulting in hepatic steatosis.
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Adenosina , Hígado Graso , Ratones Endogámicos C57BL , Material Particulado , Proteínas de Unión al ARN , Animales , Humanos , Masculino , Ratones , Adenosina/análogos & derivados , Contaminantes Atmosféricos/toxicidad , Hígado Graso/inducido químicamente , Hígado Graso/genética , Hígado Graso/metabolismo , Células Hep G2 , Hígado/metabolismo , Hígado/efectos de los fármacos , Material Particulado/toxicidad , ARN Helicasas , Metilación de ARN , ARN Mensajero/metabolismo , ARN Mensajero/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genéticaRESUMEN
N6-methyladenosine (m6A) is the most abundant modification to mRNAs. Loss-of-function studies of main m6A regulators have indicated the role of m6A in pre-mRNA splicing. Recent studies have reported the role of splicing in preventing m6A deposition. Understanding the interplay between m6A and mRNA splicing holds the potential to clarify the significance of these fundamental molecular mechanisms in cell development and function, thereby shedding light on their involvement in the pathogenesis of myriad diseases.
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Adenosina , Metilación de ARN , Empalme del ARN , ARN Mensajero , Animales , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Metiltransferasas/genética , Metiltransferasas/metabolismo , Precursores del ARN/genética , Precursores del ARN/metabolismo , Empalme del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
A high-fat diet (HFD) is a major risk factor for cardiovascular disease. However, the specific effects of a HFD on vascular inflammation and the protective role of vitexin, a bioactive compound derived from food, require further research. This study investigated the protective effects of vitexin intervention against HFD-induced vascular inflammation and its underlying mechanism. The results demonstrated that vitexin intervention significantly reduced body weight, serum total cholesterol, and low-density lipoprotein cholesterol levels in HFD-fed mice. Vitexin also improved vascular pathological changes and the inflammatory status in the mice. Furthermore, vitexin intervention reduced serum TMAO levels in HFD-fed mice by altering the gut microbiota composition. The HFD significantly increased N6-methyladenosine (m6A) levels in aorta tissues, while vitexin intervention reversed this abnormal m6A level. Through metabolite affinity responsive target fluorescence quenching and molecular docking assays, it was found that vitexin could directly bind to fat mass and obesity-associated protein (FTO), potentially promoting m6A demethylation. The dose-response relationship between TMAO and inflammation/m6A was further validated in HUVEC cells and in vivo mouse experiments. Specifically, TMAO increased m6A levels and inflammation, while vitexin inhibited TMAO-mediated m6A modification, exhibiting anti-inflammatory effects. In conclusion, this study demonstrates the protective role of vitexin against HFD-induced vascular inflammation by inhibiting TMAO-mediated RNA m6A modification, laying the foundation for the development of functional foods.
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Apigenina , Dieta Alta en Grasa , Metilaminas , Ratones Endogámicos C57BL , Animales , Ratones , Apigenina/farmacología , Masculino , Dieta Alta en Grasa/efectos adversos , Humanos , Inflamación/tratamiento farmacológico , Células Endoteliales de la Vena Umbilical Humana , ARN/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Metilación de ARNRESUMEN
N6-methyladenosine (m6A) methylation plays a crucial role in various biological processes and the pathogenesis of human diseases. However, its role and mechanism in kidney fibrosis remain elusive. In this study, we show that the overall level of m6A methylated RNA was upregulated and the m6A methyltransferase METTL3 was induced in kidney tubular epithelial cells in mouse models and human kidney biopsies of chronic kidney disease (CKD). Proximal tubule-specific knockout of METTL3 in mice protected kidneys against developing fibrotic lesions after injury. Conversely, overexpression of METTL3 aggravated kidney fibrosis in vivo. Through bioinformatics analysis and experimental validation, we identified ß-catenin mRNA as a major target of METTL3-mediated m6A modification, which could be recognized by a specific m6A reader, the insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3). METTL3 stabilized ß-catenin mRNA, increased ß-catenin protein and induced its downstream profibrotic genes, whereas either knockdown of IGF2BP3 or inhibiting ß-catenin signaling abolished its effects. Collectively, these results indicate that METTL3 promotes kidney fibrosis by stimulating the m6A modification of ß-catenin mRNA, leading to its stabilization and its downstream profibrotic genes expression. Our findings suggest that targeting METTL3/IGF2BP3/ß-catenin pathway may be a novel strategy for the treatment of fibrotic CKD.
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Fibrosis , Metiltransferasas , beta Catenina , beta Catenina/metabolismo , Animales , Ratones , Fibrosis/metabolismo , Humanos , Metilación , Metiltransferasas/metabolismo , Metiltransferasas/genética , Transducción de Señal , Adenosina/análogos & derivados , Adenosina/metabolismo , Riñón/metabolismo , Riñón/patología , Masculino , Ratones Endogámicos C57BL , Regulación hacia Arriba , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Ratones Noqueados , Metilación de ARNRESUMEN
RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating RNA splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of RNA methylation on tumor immunity. The primary types of RNA methylation encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G), and 3-methylcytidine (m3C). Compelling evidence underscores the involvement of RNA methylation in regulating the tumor microenvironment (TME). By affecting RNA translation and stability through the "writers", "erasers" and "readers", RNA methylation exerts influence over the dysregulation of immune cells and immune factors. Consequently, RNA methylation plays a pivotal role in modulating tumor immunity and mediating various biological behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed the mechanisms and functions of several RNA methylations, providing a comprehensive overview of their biological roles and underlying mechanisms within the tumor microenvironment and among immunocytes. By exploring how these RNA modifications mediate tumor immune evasion, we also examine their potential applications in immunotherapy. This review aims to provide novel insights and strategies for identifying novel targets in RNA methylation and advancing cancer immunotherapy efficacy.
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Inmunoterapia , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/metabolismo , Inmunoterapia/métodos , Metilación , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Animales , Procesamiento Postranscripcional del ARN , ARN/genética , ARN/metabolismo , Regulación Neoplásica de la Expresión Génica , Metilación de ARNRESUMEN
Accurate diagnosis of ulcerative colitis (UC) and Crohn's disease (CD), the main subtypes of inflammatory bowel disease (IBD), has been challenging due to the constraints of the current techniques. N6-methyl adenosine (m6A) regulators have evolved as key players in IBD pathogenesis; however, their relation to its clinical setting is largely unexplored. This study investigated the potential of selected RNA methylation machinery and m6A target genes as serum biomarkers of UC and CD, their predictive and discriminating capabilities, and their correlations with laboratory data, interleukin (IL)-6, interferon-γ, disease activity scores, and pathological features. Fifty UC and 45 CD patients, along with 30 healthy volunteers were enlisted. The mRNA expression levels of the m6A writers methyltransferase-like 3 (METTL3) and Wilms-tumor associated protein (WTAP), and the reader YTH domain family, member 1 (YTHDF1), along with the m6A candidate genes sex determining region Y-box 2 (SOX2), hexokinase 2 (HK2), and ubiquitin-conjugating enzyme E2 L3 (UBE2L3) were upregulated in UC patients, whereas only METTL3, HK2, and UBE2L3 were upregulated in CD patients versus controls. Serum WTAP (AUC = 0.94, 95 %CI = 0.874-1.006) and HK2 (AUC = 0.911, 95 %CI = 0.843-0.980) expression levels showed excellent diagnostic accuracy for UC, METTL3 showed excellent diagnostic accuracy for CD (AUC = 0.91, 95 %CI = 0.828-0.992), meanwhile, WTAP showed excellent discriminative power between the two diseases (AUC = 0.91, 95 %CI = 0.849-0.979). Multivariate logistic analysis unveiled the association of METTL3 and UBE2L3 expression with the risk of CD and UC diagnosis, respectively, controlled by age and sex as confounders. Remarkable correlations were recorded between the gene expression of studied m6A regulators and targets in both diseases. Among UC patients, serum METTL3 and WTAP were correlated with UC extent/type, while WTAP was correlated with IL-6. Among CD patients, serum METTL3 and HK2 were correlated with CD activity index (CDAI) and CD location. In conclusion, m6A regulators and target genes are distinctly expressed in UC and CD clinical samples, correlate with disease activity and extent/location, and could serve as a novel approach to empower the diagnosis and stratification of IBD subtypes.