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: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: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: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: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: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
Project description:N6-methyladenosine (m6A) modification is the most universal and abundant post-transcriptional modification of eukaryotic RNA and occurs mainly at the consensus motif RR (m6A) CH (R = A or G, H = A, C, or U) in long internal exons, near stop codons, or in the 3' untranslated region (UTR). "Writers," "erasers," and "readers" are responsible for the occurrence, removal, and recognition of m6A modification, respectively. Substantial evidence has shown that m6A RNA modification can exert important functions in physiological and pathological processes. Cardiovascular diseases (CVDs) are a wide array of disorders affecting heart or vessels, including atherosclerosis (AS), hypertension (HT), ischemia/reperfusion (I/R) injury, myocardial infarction (MI), stroke, cardiac hypertrophy, heart failure (HF), and so on. Despite the advances in lipid-lowering drugs, antihypertensives, antiplatelet agents, and anticoagulation therapy, CVDs are still the leading cause of death worldwide. Recent studies have suggested that m6A modification of RNA may contribute to the pathogenesis of CVDs, providing a novel research insight for CVDs. Herein, we provide an up-of-date summarization of the molecular mechanism of m6A and the roles of m6A in different types of CVDs. At last, we propose that m6A might be a potiential biomarker or therapeutic target for CVDs.
| S-EPMC9098837 | biostudies-literature
Project description:In recent years, with the development of RNA sequencing technology and bioinformatics methods, the epigenetic modification of RNA based on N6-methyladenosine (m6A) has gradually become a research hotspot in the field of bioscience. m6A is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs). m6A methylation modification can dynamically and reversibly regulate RNA transport, localization, translation and degradation through the interaction of methyltransferase, demethylase and reading protein. m6A methylation can regulate the expression of proto-oncogenes and tumor suppressor genes at the epigenetic modification level to affect tumor occurrence and metastasis. The morbidity and mortality of esophageal cancer (EC) are still high worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common tissue subtype of EC. This article reviews the related concepts, biological functions and recent advances of m6A methylation in ESCC, and looks forward to the prospect of m6A methylation as a new diagnostic biomarker and potential therapeutic target for ESCC.
| S-EPMC8353866 | biostudies-literature
Project description:Epigenetic mRNA modification is an evolving field. N6-methyladenosine (m6A) is the most frequent internal transcriptional modification in eukaryotic messenger RNAs (mRNAs). This review will discuss the functions of the m6A mRNA machinery, including its "writers" that are components of the methyltransferase complex, its "readers" and its "erasers" (specifically FTO and ALKBH5) in cancer. The writers deposit the m6A and include METTL3, METTL14, WTAP, VIRMA, and RBM15. M6A methylation is removed by the m6A demethylases (FTO and ALKBH5). Lastly, the most diverse members are the readers that can contribute to mRNA splicing, stability, translation, and nuclear export. Many of these functions continue to be elucidated. The dysregulation of this machinery in various malignancies and the associated impact on tumorigenesis and drug response will be discussed herein with a focus on solid tumors. It is clear that, by contributing to either mRNA stability or translation, there are downstream targets that are impacted, contributing to cancer progression and the self-renewal ability of cancer stem cells.
| S-EPMC8627172 | biostudies-literature