RNA Modification by m6A Methylation in Cardiovascular Disease.
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ABSTRACT:
SUBMITTER: Chen J
PROVIDER: S-EPMC8183103 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cardiovascular diseases (CVDs) remain the leading cause of death and disability worldwide, despite marked improvements in prevention, diagnosis, and early intervention. There is an urgent need to discover more effective therapeutic strategies, which would be facilitated by a more in-depth understanding of CVDs and their underlying molecular mechanisms. Recent advances in knowledge about epigenetic mechanisms, especially RNA methylation, have revealed a close relationship between epigenetic modifications and CVDs and have brought to potential novel targets for diagnosis and treatment. Here, we provide a review of recent studies exploring RNA N6-methyladenosine (m6A) modification, with particular emphasis on its role in CVDs, such as coronary heart disease, hypertension, cardiac hypertrophy, and heart failure. We also introduce the "life cycle" of m6A and its dominant function in several biological processes. Finally, we highlight the prospects of treatment based on interfering with m6A, which could have a transformative effect on clinical medicine.
| S-EPMC7544996 | biostudies-literature
Project description:BackgroundN6-methyladenosine (m6A) is the most frequent internal methylation of eukaryotic RNA (ribonucleic acid) transcripts and plays an important function in RNA processing. The current research aimed to investigate the role of m6A-STIM2 axis in cholangiocarcinoma (CCA) progression.MethodsThe expression of STIM2 (Stromal Interaction Molecule 2) in CCA was measured using quantitative polymerase chain reaction (PCR) and immunohistochemistry (IHC). STIM2 was examined in vivo for its effects on the malignant phenotypes of CCA cells. The m6A modification of STIM2 was assessed through MeRIP (methylated RNA Immunoprecipitation)-PCR.ResultsBased on the GEPIA (Gene Expression Profiling Interactive Analysis) 2 database findings, a low STIM2 mRNA (messenger RNA) level was related to a poor prognosis in individuals with CCA. Quantitative PCR and IHC assays indicated decreased protein satin in CCA tissues and were associated with extrahepatic metastasis. Vianude mice tail vein injection model indicated that increased STIM2 levels suppressed CCA cell metastasis in vivo, while KRT8 (keratin 8) was detected as the direct downstream target of STIM2-mediated CCA cell metastasis in vivo. Meanwhile, based on SRAMP database and MeRIP assays indicated that m6A alteration resulted in abnormal STIM2 expression in CCA via METTL14 and YTHDC2.ConclusionsOur findings revealed the epi-transcriptomic dysregulation in CCA and metastasis by proposing a complicated STIM2-KRT8 regulatory paradigm based on m6A alteration.
| S-EPMC8848379 | biostudies-literature
Project description:N6‑methyladenosine (m6A) is the most prevalent and abundant type of internal post‑transcriptional RNA modification in eukaryotic cells. Multiple types of RNA, including mRNAs, rRNAs, tRNAs, long non‑coding RNAs and microRNAs, are involved in m6A methylation. The biological function of m6A modification is dynamically and reversibly mediated by methyltransferases (writers), demethylases (erasers) and m6A binding proteins (readers). The methyltransferase complex is responsible for the catalyzation of m6A modification and is typically made up of methyltransferase‑like (METTL)3, METTL14 and Wilms tumor 1‑associated protein. Erasers remove methylation by fat mass and obesity‑associated protein and ALKB homolog 5. Readers play a role through the recognition of m6A‑modified targeted RNA. The YT521‑B homology domain family, heterogeneous nuclear ribonucleoprotein and insulin‑like growth factor 2 mRNA‑binding protein serve as m6A readers. The m6A methylation on transcripts plays a pivotal role in the regulation of downstream molecular events and biological functions, such as RNA splicing, transport, stability and translatability at the post‑transcriptional level. The dysregulation of m6A modification is associated with cancer, drug resistance, virus replication and the pluripotency of embryonic stem cells. Recently, a number of studies have identified aberrant m6A methylation in cardiovascular diseases (CVDs), including cardiac hypertrophy, heart failure, arterial aneurysm, vascular calcification and pulmonary hypertension. The aim of the present review article was to summarize the recent research progress on the role of m6A modification in CVD and give a brief perspective on its prospective applications in CVD.
| S-EPMC7595665 | biostudies-literature
Project description:Impaired gene regulation lies at the heart of many disorders, including developmental diseases and cancer. Furthermore, the molecular pathways that control gene expression are often the target of cellular parasites, such as viruses. Gene expression is controlled through multiple mechanisms that are coordinated to ensure the proper and timely expression of each gene. Many of these mechanisms target the life cycle of the RNA molecule, from transcription to translation. Recently, another layer of regulation at the RNA level involving RNA modifications has gained renewed interest of the scientific community. The discovery that N6-methyladenosine (m6A), a modification present in mRNAs and long noncoding RNAs, can be removed by the activity of RNA demethylases, launched the field of epitranscriptomics; the study of how RNA function is regulated through the addition or removal of post-transcriptional modifications, similar to strategies used to regulate gene expression at the DNA and protein level. The abundance of RNA post-transcriptional modifications is determined by the activity of writer complexes (methylase) and eraser (RNA demethylase) proteins. Subsequently, the effects of RNA modifications materialize as changes in RNA structure and/or modulation of interactions between the modified RNA and RNA binding proteins or regulatory RNAs. Disruption of these pathways impairs gene expression and cellular function. This review focuses on the links between the RNA modification m6A and its implications in human diseases.
| S-EPMC5487527 | biostudies-literature
Project description:N6-methyladenosine (m6A), the most prevalent post-transcriptional RNA modification throughout the eukaryotic transcriptome, participates in diverse biophysiological processes including cell fates, embryonic development and stress responses. Accumulating evidence suggests that m6A modification in neural development and differentiation are highly regulated processes. As RNA m6A is crucial to protein translation and various bioprocesses, its modification dysregulation may also be associated with brain injury. This review highlights the biological significance of m6A modification in neurodegenerative disease and brain injury, including cerebrovascular disorders, is highlighted. Emphasis is placed on recent findings that elucidate the relevant molecular functional mechanism of m6A modification after brain injury and neurodegenerative disease. Finally, a neurobiological basis for further investigation of potential treatments is described.
| S-EPMC9493472 | biostudies-literature
Project description:BackgroundFew studies have been reported the potential role of N6-methyladenosine (m6A) modification in osteoarthritis (OA). We investigated the patterns of m6A modification in the immune microenvironment of OA.MethodsWe evaluated the m6A modification patterns based on 22 m6A regulators in 139 OA samples and systematically associated these modification patterns with immune cell infiltration characteristics. The function of m6A phenotype-related differentially expressed genes (DEGs) was investigated using gene enrichment analysis. An m6A score model was constructed using principal component analysis (PCA), and an OA prediction model was established based on the key m6A regulators. We used real-time PCR analysis to detect the changes of gene expression in the cell model of OA.ResultsHealthy and OA samples showed significant differences in the expression of m6A regulators. Nine key m6A regulators, two m6A modification patterns, m6A-related genes and two gene clusters were identified. Some m6A regulators had a strong correlation with each other. Gene clusters and m6A clusters have high similarity, and cluster A corresponds to a high m6A score. Immunocytes infiltration differed significantly between the two clusters, with the m6A cluster B and gene cluster B having more types of infiltrating immunocytes than cluster A. The predictive model can also predict the progression of OA through m6A regulators expression. The results of real-time PCR analysis showed that the gene expression in the cell model of OA is similar to that of the m6A cluster B.ConclusionsOur study reveals for the first time the potential regulatory mechanism of m6A modification in the immune microenvironment of OA. This study also sheds new light on the pathogenesis of OA.
| S-EPMC9728527 | biostudies-literature
Project description:BackgroundThere is growing evidence to demonstrate that the epigenetic regulation of immune characteristics, especially for N6-methyladenosine (m6A) RNA methylation. However, how m6A methylation is involved in lupus nephritis (LN) is still unclear. This study aimed to determine the role of m6A RNA methylation and their association with the immune microenvironment in LN.MethodsIn total, 87 glomeruli (73 LN, 14 living healthy donors), 110 tubulointerstitium (95 LN, 15 living healthy donors), and 21 kidney whole tissue samples (14 LN, 7 controls) were included in our research to evaluate the expression levels of m6A regulators. CIBERSORT was used to assess the abundance of infiltrating immunocytes. The m6A regulator gene signature for LN was identified using LASSO-logistic regression and verified with external data. Consensus clustering algorithms were used for the unsupervised cluster analysis of m6A modification patterns in LN. Single-sample gene-set enrichment analysis and gene set variation analysis algorithms were employed to assess the activity of immune responses and other functional pathways. Weighted gene co-expression network analysis and protein-protein interaction networks were used to identify m6A methylation markers. Lastly, the Nephroseq V5 tool was used to analyze the correlation between m6A markers and renal function.ResultsWe found that the expression of m6A regulators was more significantly different in the glomeruli in LN compared with tubulointerstitium and whole kidney tissue. We established an m6A regulator signature, comprised of METTL3, WTAP, YTHDC2, YTHDF1, FMR1, and FTO, that can easily distinguish LN and healthy individuals. Two distinct m6A modification patterns based on 18 m6A regulators were determined, with significant differences in m6A regulator expression, immune microenvironment, biological functional pathways, and clinical characteristics. Activated NK cells, most immune responses, and HLA genes had strong correlations with m6A regulators. Seven m6A markers were identified and demonstrated a meaningful correlation with GFR, indicating that they are potential prognostic biomarkers.ConclusionThis study emphasized that m6A RNA methylation and the immune microenvironment are closely linked in LN. A better understanding of m6A modification patterns provide a basis for the development of novel therapeutic options for LN.
| S-EPMC8454410 | biostudies-literature
Project description:RNA N6-methyladenosine (m6A), the most abundant internal modification of mRNAs, plays key roles in human development and health. Post-translational methylation of proteins is often critical for the dynamic regulation of enzymatic activity. However, the role of methylation of the core methyltransferase METTL3/METTL14 in m6A regulation remains elusive. We find by mass spectrometry that METTL14 arginine 255 (R255) is methylated (R255me). Global mRNA m6A levels are greatly decreased in METTL14 R255K mutant mouse embryonic stem cells (mESCs). We further find that R255me greatly enhances the interaction of METTL3/METTL14 with WTAP and promotes the binding of the complex to substrate RNA. We show that protein arginine N-methyltransferases 1 (PRMT1) interacts with and methylates METTL14 at R255, and consistent with this, loss of PRMT1 reduces mRNA m6A modification globally. Lastly, we find that loss of R255me preferentially affects endoderm differentiation in mESCs. Collectively, our findings show that arginine methylation of METTL14 stabilizes the binding of the m6A methyltransferase complex to its substrate RNA, thereby promoting global m6A modification and mESC endoderm differentiation. This work highlights the crosstalk between protein methylation and RNA methylation in gene expression.
| S-EPMC8213825 | biostudies-literature
Project description:It is known that heat stress induces various physiological challenges in livestock production including changes in lipid metabolism. However, the molecular mechanism of how heat stress regulates lipid metabolism at the mRNA level is still largely unknown. N6-methyl-adenosine (m6A) is the most common and abundant modification on RNA molecules present in eukaryotes, which affects almost all aspects of RNA metabolism and thus gives us the hint that it may participate in changes of gene expression of lipid metabolism during heat stress. Therefore, the purpose of the present study was to investigate the effect of heat stress on fat metabolism in 21-day Large White × Landrace piglets from sows challenged by heat stress from day 85 of gestation until day 21 of lactation. We measured the expression of heat shock proteins (HSPs), genes associated with lipid metabolism, m6A-related enzymes, and m6A levels in abdominal fat and liver of offspring piglets. Our results showed that high ambient temperature significantly increased the expression of HSP70 (P < 0.01) in both liver and abdominal fat and upregulated HSP27 in the liver (P < 0.05). Additionally, genes involved in fat metabolism such as ACACA, FASN, DGAT1, PPAR-γ, SREBP-1c, and FABP4 were upregulated in abdominal fat in the experimental group challenged by high ambient temperature. In the liver, heat stress increased the mRNA expression of DGAT1, SREBP-1c, and CD36 and decreased ATGL and CPT1A expression (P < 0.05). The m6A level was higher in the heat stress group compared with the control group in the liver and abdominal fat of offspring piglets (P < 0.01). Notably, heat stress also increased gene expression of METTL14, WTAP, FTO, and YTHDF2 (P < 0.05) in both abdominal fat and liver. The protein abundances of METTL3, METTL14, and FTO were upregulated after heat stress in abdominal fat (P < 0.05) but not in the liver. Although there was no difference in the protein abundance of YTHDF2 in abdominal fat, its level was increased in the liver (P < 0.05). In conclusion, our findings showed that heat stress increased expression of genes involved in lipogenesis, which provided scientific evidence to the observation of increased fatness in pigs under heat stress. We also demonstrated a possible mechanism that m6A RNA modification may be associated with these changes in lipid metabolism upon heat stress.
| S-EPMC6527640 | biostudies-literature
Project description:N1-methyladenosine (m1A) is a prevalent and reversible post-transcriptional RNA modification that decorates tRNA, rRNA and mRNA. Recent studies based on technical advances in analytical chemistry and high-throughput sequencing methods have revealed the crucial roles of m1A RNA modification in gene regulation and biological processes. In this review, we focus on progress in the study of m1A methyltransferases, m1A demethylases and m1A-dependent RNA-binding proteins and highlight the biological mechanisms and functions of m1A RNA modification, as well as its association with human disease. We also summarize the current understanding of detection approaches for m1A RNA modification.
| S-EPMC9141559 | biostudies-literature