Search Results (25)

Negative-sense RNA viruses comprise a wide array of viral families, such as Orthomyxoviridae, Paramyxoviridae, Rhabdoviridae, and Morbillivirus, all of which are adept at inciting significant epidemic outbreaks. Throughout their replication cycle, these viruses engage in a variety of RNA modifications, during both the co-transcriptional and post-transcriptional phases, which are mediated by specific enzymatic activities. These chemical alterations play a critical role in shaping viral fitness, particularly in terms of evading innate immune responses. Key chemical modifications, such as adenosine methylation, 2′-O methylation of nucleosides, and adenosine-to-inosine editing, play critical roles in determining the stability, translational efficiency, and immune recognition of viral RNA. These modifications can reduce the activation of immune sensors, thereby suppressing interferon production and broader antiviral responses. In contrast, certain modifications may enhance immune recognition, which opens avenues for novel vaccine and antiviral strategy development. A comprehensive understanding of these RNA chemical modifications and their implications for virus–host interactions is essential for advancing therapeutic strategies aimed at manipulating innate immunity and optimizing the efficacy of RNA-based vaccines. This review examines the mechanisms and implications of RNA chemical modifications in negative-sense RNA viruses, emphasizing their dual roles in either evading or activating the innate immune system. Full article

Osteoarthritis (OA) is a chronic joint disorder characterized by progressive degeneration of articular cartilage, pain, synovial inflammation, and bone remodeling. Post-transcriptional RNA modifications, known as epitranscriptome, are a group of biochemical alterations in the primary RNA transcript that might influence RNA structure, stability, and function. Different kinds of RNA modifications have been recognized, such as methylation, acetylation, pseudouridylation, and phosphorylation. N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), 2′-O-ribose methylation (2′-O-Me), and pseudouridylation (Ψ) are the most prevalent RNA modifications. Recent studies have shown that disruption in these modifications can interfere with gene expression and protein function. Here, we will review all types of RNA modifications and how they contribute to the onset and progression of OA. To the best of our knowledge, this is the first review comprehensively addressing all epitranscriptomic modifications in OA. Full article

Background: Significant sex differences exist in atrial fibrillation (AF). Better understanding of its underlying mechanism would help AF management. This study aimed to investigate the contribution of circulating metabolites to sex differences in AF and the association between them. Methods: A total of 108 patients with AF were enrolled. Untargeted metabolomics were performed in plasma samples of male and female patients. Correlation analysis with clinical characteristics and Mendelian randomization were used to identify sex-specific metabolites associated with AF, which was further validated in additional patients. Transcriptomics data of the left atrium were used to investigate the molecular alteration of the left atrium responding to identified sex-specific circulating metabolites. The effect of selected sex-specific metabolites on cardiomyocytes was further investigated. Results: A total of 60 annotated metabolites were found with different levels between male and female patients. Among these sex-specific metabolites, three metabolites, 7-Methylguanosine, succinic acid, and N-Undecylbenzenesulfonic acid, were positively related to the left atrial remodeling. Additionally, succinic acid was significantly associated with increased risk of AF (OR = 1.26; 95% CI: 1.13 to 1.40; p < 0.001). And, SUCLA2, the gene of succinic acid metabolism, was significantly increased in the left atrium of male patients (fold change = 1.53; p = 0.008). Treatment with succinic acid led to cardiomyocyte hypertrophy and mitochondrial dysfunction. Conclusions: This study highlights sex differences in circulating metabolites in patients with AF and identifies the associations between sex-specific metabolites and AF. succinic acid, which is much higher in male patients, contributes to the process of AF. Full article

Epitranscriptomic mechanisms, which constitute an important layer in post-transcriptional gene regulation, are involved in numerous cellular processes under health and disease such as stem cell development or cancer. Among various such mechanisms, RNA methylation is considered to have vital roles in eukaryotes primarily due to its dynamic and reversible nature. There are numerous RNA methylations that include, but are not limited to, 2’-O-dimethyladenosine (m⁶Am), N⁷-methylguanosine (m⁷G), N⁶-methyladenosine (m⁶A) and N¹-methyladenosine (m¹A). These biochemical modifications modulate the fate of RNA by affecting the processes such as translation, target site determination, RNA processing, polyadenylation, splicing, structure, editing and stability. Thus, it is highly important to quantitatively measure the changes in RNA methylation marks to gain insight into cellular processes under health and disease. Although there are complicating challenges in identifying certain methylation marks genome wide, various methods have been developed recently to facilitate the quantitative measurement of methylated RNAs. To this end, the detection methods for RNA methylation can be classified in five categories such as antibody-based, digestion-based, ligation-based, hybridization-based or direct RNA-based methods. In this review, we have aimed to summarize our current understanding of the detection methods for RNA methylation, highlighting their advantages and disadvantages, along with the current challenges in the field. Full article

Epitranscriptomics refers to post-transcriptional regulation of gene expression via RNA modifications and editing that affect RNA functions. Many kinds of modifications of mRNA have been described, among which are N6-methyladenosine (m6A), N1-methyladenosine (m1A), 7-methylguanosine (m7G), pseudouridine (Ψ), and 5-methylcytidine (m5C). They alter mRNA structure and consequently stability, localization and translation efficiency. Perturbation of the epitranscriptome is associated with human diseases, thus opening the opportunity for potential manipulations as a therapeutic approach. In this review, we aim to provide an overview of the functional roles of epitranscriptomic marks in the skeletal muscle system, in particular in embryonic myogenesis, muscle cell differentiation and muscle homeostasis processes. Further, we explored high-throughput epitranscriptome sequencing data to identify RNA chemical modifications in muscle-specific genes and we discuss the possible functional role and the potential therapeutic applications. Full article

The role of N7-methylguanosine(m7G)-related miRNAs in lung adenocarcinoma (LUAD) remains unclear. We used LUAD data from The Cancer Genome Atlas (TCGA) to establish a risk model based on the m7G-related miRNAs, and divided patients into high-risk or low-risk subgroups. A nomogram for predicting overall survival (OS) was then constructed based on the independent risk factors. In addition, we performed a functional enrichment analysis and defined the oxidative stress-related genes, immune landscape as well as a drug response profile in the high-risk and low-risk subgroups. This study incorporated 28 m7G-related miRNAs into the risk model. The data showed a significant difference in the OS between the high-risk and low-risk subgroups. The receiver operating characteristic curve (ROC) predicted that the area under the curve (AUC) of one-year, three-year and five-year OS was 0.781, 0.804 and 0.853, respectively. The C-index of the prognostic nomogram for predicting OS was 0.739. We then analyzed the oxidative stress-related genes and immune landscape in the high-risk and low-risk subgroups. The data demonstrated significant differences in the expression of albumin (ALB), estimated score, immune score, stromal score, immune cell infiltration and functions between the high-risk and low-risk subgroups. In addition, the drug response analysis showed that low-risk subgroups may be more sensitive to tyrosine kinase inhibitor (TKI) and histone deacetylase (HDAC) inhibitors. We successfully developed a novel risk model based on m7G-related miRNAs in this study. The model can predict clinical prognosis and guide therapeutic regimens in patients with LUAD. Our data also provided new insights into the molecular mechanisms of m7G in LUAD. Full article

N7-Methylguanosine (m7G) modification holds significant importance in regulating posttranscriptional gene expression in epigenetics. Long non-coding RNAs (lncRNAs) have been demonstrated to play a crucial role in cancer progression. m7G-related lncRNA may be involved in the progression of pancreatic cancer (PC), although the underlying mechanism of regulation remains obscure. We obtained RNA sequence transcriptome data and relevant clinical information from the TCGA and GTEx databases. Univariate and multivariate Cox proportional risk analyses were performed to build a twelve-m7G-associated lncRNA risk model with prognostic value. The model was verified using receiver operating characteristic curve analysis and Kaplan–Meier analysis. The expression level of m7G-related lncRNAs in vitro was validated. Knockdown of SNHG8 increased the proliferation and migration of PC cells. Differentially expressed genes between high- and low-risk groups were identified for gene set enrichment analysis, immune infiltration, and potential drug exploration. We conducted an m7G-related lncRNA predictive risk model for PC patients. The model had independent prognostic significance and offered an exact survival prediction. The research provided us with better knowledge of the regulation of tumor-infiltrating lymphocytes in PC. The m7G-related lncRNA risk model may serve as a precise prognostic tool and indicate prospective therapeutic targets for PC patients. Full article

With the increasingly serious burden of osteoarthritis (OA) on modern society, it is urgent to propose novel diagnostic biomarkers and differentiation models for OA. 7-methylguanosine (m⁷G), as one of the most common base modification forms in post transcriptional regulation, through which the seventh position N of guanine (G) of messenger RNA is modified by methyl under the action of methyltransferase; it has been found that it plays a crucial role in different diseases. Therefore, we explored the relationship between OA and m⁷G. Based on the expression level of 18 m⁷G-related regulators, we identified nine significant regulators. Then, via a series of methods of machine learning, such as support vector machine recursive feature elimination, random forest and lasso-cox regression analysis, a total of four significant regulators were further identified (DCP2, EIF4E2, LARP1 and SNUPN). Additionally, according to the expression level of the above four regulators, two different m⁷G-related clusters were divided via consensus cluster analysis. Furthermore, via immune infiltration, differential expression analysis and enrichment analysis, we explored the characteristic of the above two different clusters. An m⁷G-related scoring model was constructed via the PCA algorithm. Meanwhile, there was a different immune status and correlation for immune checkpoint inhibitors between the above two clusters. The expression difference of the above four regulators was verified via real-time quantitative polymerase chain reaction. Overall, a total of four biomarkers were identified and two different m⁷G-related subsets of OA with different immune microenvironment were obtained. Meanwhile, the construction of m⁷G-related Scoring model may provide some new strategies and insights for the therapy and diagnosis of OA patients. Full article

The existence of the thiouridine synthetase, methyltransferase and pseudouridine synthase (THUMP) domain was originally predicted by a bioinformatic study. Since the prediction of the THUMP domain more than two decades ago, many tRNA modification enzymes containing the THUMP domain have been identified. According to their enzymatic activity, THUMP-related tRNA modification enzymes can be classified into five types, namely 4-thiouridine synthetase, deaminase, methyltransferase, a partner protein of acetyltransferase and pseudouridine synthase. In this review, I focus on the functions and structures of these tRNA modification enzymes and the modified nucleosides they produce. Biochemical, biophysical and structural studies of tRNA 4-thiouridine synthetase, tRNA methyltransferases and tRNA deaminase have established the concept that the THUMP domain captures the 3′-end of RNA (in the case of tRNA, the CCA-terminus). However, in some cases, this concept is not simply applicable given the modification patterns observed in tRNA. Furthermore, THUMP-related proteins are involved in the maturation of other RNAs as well as tRNA. Moreover, the modified nucleosides, which are produced by the THUMP-related tRNA modification enzymes, are involved in numerous biological phenomena, and the defects of genes for human THUMP-related proteins are implicated in genetic diseases. In this review, these biological phenomena are also introduced. Full article

The aim of the study was to evaluate the effect of selected polyphenolic compounds: epicatechin, apigenin, and naringenin, administered separately or in combination with zinc (Zn), on the growth and development of the neoplastic process induced by 7,12-dimethylbenz[a]anthracene (DMBA) in rats. The impact of supplementation with the above-mentioned compounds on the content of modified derivatives: 1-methyladenosine, N6-methyl-2’-deoxyadenosine, O-methylguanosine, 7-methylguanine, 3-methyladenine, 1-methylguanine, 2-amino-6,8-dihydroxypurine, and 8-hydroxy-2’-deoxyguanosine in the urine of rats with mammary cancer was also assessed. Female Sprague-Dawley rats divided into 7 groups were used in the study: animals without supplementation and animals supplemented with apigenin, epicatechin, and naringenin separately or in combination with zinc. To induce mammary cancer, rats were treated with DMBA. Modified derivatives were determined by a validated high-performance liquid chromatography coupled to mass spectrometry method. Based on the obtained results, it can be said that supplementation of the animals with naringenin inhibits the development and progression of the neoplastic process in rats treated with 7,12-dimethylbenzanthracene. Neoplastic tumors were found in only 2 of 8 rats (incidence: 25%) and were considered to be at most grade 1 malignancy. The first palpable tumors in the group of animals receiving naringenin appeared two–three weeks later when compared to other groups. The combination of zinc with flavonoids (apigenin, epicatechin, and naringenin) seems to stimulate the process of carcinogenesis. The level of N6-methyl-2’-deoxyadenosine and 3-methyladenine in the urine of rats was statistically significantly higher in the groups supplemented with apigenin, epicatechin, and naringenin administered in combination with Zn than in the groups receiving only polyphenolic compounds. In conclusion, supplementation of rats with selected flavonoids administered separately or in combination with Zn has an impact on the development of neoplasms and the level of modified nucleosides in the urine of rats with breast cancer. Our results raise the question of whether simultaneous diet supplementation with more than one anti-cancer agent may reduce/stimulate the risk of carcinogenesis. Full article

(1) Background: It is well-known that long non-coding RNAs (lncRNAs) and N7-methylguanosine (m7G) contribute to hepatocellular carcinoma (HCC) progression. However, it remains unclear whether lncRNAs regulating m7G modification could predict HCC prognosis. Thus, we sought to explore the prognostic implications of m7G-related lncRNAs in HCC patients. (2) Methods: Prognostic M7G-related lncRNAs obtained from The Cancer Genome Atlas (TCGA) database were screened by co-expression analysis and univariate Cox regression analysis. Next, the m7G-related lncRNA signature (m7GRLSig) was conducted by Least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression analysis. Kaplan–Meier analysis and time-dependent receiver operating characteristics (ROC) assessed the prognostic abilities of our signature. Univariate and multivariate Cox regression, nomogram, and principal component analysis (PCA) were conducted to evaluate our signature. Subsequently, we investigated the role of m7GRLSig on the immune landscape and sensitivity to drugs in HCC patients. The potential function of lncRNAs obtained from the prognostic signature was explored by in vitro experiments. (3) Results: A novel m7GRLSig was identified using seven meaningful lncRNA (ZFPM2-AS1, AC092171.2, PIK3CD-AS2, NRAV, CASC19, HPN-AS1, AC022613.1). The m7GLPSig exhibited worse survival in the high-risk group and served as an independent prognostic factor. The m7GRLSig stratification was sensitive in assessing the immune landscape and sensitivity to drugs between the high-risk and low-risk groups. Finally, in vitro experiments confirmed that the knockdown of NRAV was accompanied by the downregulation of METTL1 during HCC progression. (4) Conclusions: The m7G-related signature is a potential predictor of HCC prognosis and contributes to individualize the effective drug treatment of HCC. Full article

Chronic lung diseases are highly prevalent worldwide and cause significant mortality. Lung cancer is the end stage of many chronic lung diseases. RNA epigenetics can dynamically modulate gene expression and decide cell fate. Recently, studies have confirmed that RNA epigenetics plays a crucial role in the developing of chronic lung diseases. Further exploration of the underlying mechanisms of RNA epigenetics in chronic lung diseases, including lung cancer, may lead to a better understanding of the diseases and promote the development of new biomarkers and therapeutic strategies. This article reviews basic information on RNA modifications, including N⁶ methylation of adenosine (m⁶A), N¹ methylation of adenosine (m¹A), N⁷-methylguanosine (m⁷G), 5-methylcytosine (m⁵C), 2′O-methylation (2′-O-Me or Nm), pseudouridine (5-ribosyl uracil or Ψ), and adenosine to inosine RNA editing (A-to-I editing). We then show how they relate to different types of lung disease. This paper hopes to summarize the mechanisms of RNA modification in chronic lung disease and finds a new way to develop early diagnosis and treatment of chronic lung disease. Full article

Colon cancer (CC), one of the most common malignancies worldwide, lacks an effective prognostic prediction biomarker. N7-methylguanosine (m7G) methylation is a common RNA modification type and has been proven to influence tumorigenesis. However, the correlation between m7G-related genes and CC remains unclear. The gene expression levels and clinical information of CC patients were downloaded from public databases. Twenty-nine m7G-related genes were obtained from the published literature. Via unsupervised clustering based on the expression levels of m7G-related genes, CC patients were divided into three m7G clusters. Based on differentially expressed genes (DEGs) from the above three groups, CC patients were further divided into three gene clusters. The m7G score, a prognostic model, was established using principal component analysis (PCA) based on 15 prognosis-associated m7G genes. KM curve analysis demonstrated that the overall survival rate was remarkably higher in the high-m7G score group, which was much more significant in advanced CC patients as confirmed by subgroup analysis. Correlation analysis indicated that the m7G score was associated with tumor mutational burden (TMB), PD-L1 expression, immune infiltration, and drug sensitivity. The expression level of prognosis-related m7G genes was further confirmed in human CC cell lines and samples. This study established an m7G gene-based prognostic model (m7G score), which demonstrated the important roles of m7G-related genes during CC initiation and progression. The m7G score could be a practical biomarker to predict immunotherapy response and prognosis in CC patients. Full article

Although N7-methylguanosine (m7G) modification serves as a tumor promoter in bladder cancer (BLCA), the comprehensive role of m7G-related characterization in BLCA remains unclear. In this study, we systematically evaluated the m7G-related clusters of 760 BLCA patients through consensus unsupervised clustering analysis. Next, we investigated the underlying m7G-related genes among these m7G-related clusters. Univariate Cox and LASSO regressions were used for screening out prognostic genes and for reducing the dimension, respectively. Finally, we developed a novel m7G-related scoring system via the GSVA algorithm. The correlation between tumor microenvironment, prediction of personalized therapies and this m7G-related signature was gradually revealed. We first identified three m7G-related clusters and 1108 differentially expressed genes relevant to the three clusters. Based on the profile of 1108 genes, we divided BLCA patients into two clusters, which were quantified by our established m7G-related scoring system. Patients with higher m7G-related scores tended to have a better OS and more chances to benefit from immunotherapy. A significantly negative connection between sensitivity to classic chemotherapeutic drugs and m7G-related signature was uncovered. In summary, our data show that m7G-related characterization of BLCA patients can be of value for prognostic stratification and for patient-oriented therapeutic options, designing personalized treatment strategies in the preclinical setting. Full article

RNA methylation plays a vital role in the pathogenesis of a variety of diseases including cancer, and aberrant levels of modified nucleosides in RNA were revealed to be related to cancer. Urine is a favored source for biomarker discovery due to the non-invasion to patients. Herein, we developed a sensitive hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC–MS/MS) method combined with stable isotope dilution for accurate quantification of methylated nucleosides in human urine. With this method, we successfully quantified ten methylated nucleosides in urine samples collected from healthy controls and breast cancer patients. We found N⁶-methyladenosine (m⁶A), 2′-O-methyladenosine (A_m), N¹-methyladenosine (m¹A), N⁶,2′-O-dimethyladenosine (m⁶A_m), N¹-methylguanosine (m¹G), 2′-O-methylguanosine (G_m), 5-methylcytidine (m⁵C) and 2′-O-methylcytidine (C_m) were all decreased in early-stage breast cancer patients, and a nomogram prediction model was constructed. Locally advanced breast cancer patients exhibited elevated levels of urinary 2′-O-methylated nucleosides in comparison to early-stage breast cancer patients. Together, we developed a robust method for the simultaneous determination of methylated nucleosides in human urine, and the results revealed an association between the contents of urinary methylated nucleosides and the occurrence of breast cancer, which may stimulate future studies about the regulatory roles of these methylated nucleosides in the initiation and progression of breast cancer. Full article