Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Abstract

Background: Myocardial infarction (MI) is one of the leading threats to human health. N6-methyladenosine (m6A) modification, as a pivotal regulator of messenger RNA stability, protein expression, and cellular processes, exhibits important roles in the development of cardiac remodeling and cardiomyocyte contractile function.Methods: The expression levels of m6A regulators were analyzed using the GSE5406 database. We analyzed genome-wide association study data and single-cell sequencing data to confirm the functional importance of m6A regulators in MI. Three molecular subtypes with different clinical characteristics were established to tailor treatment strategies for patients with MI. We applied pathway analysis and differentially expressed gene (DEG) analysis to study the changes in gene expression and identified four common DEGs. Furthermore, we constructed the protein–protein interaction network and confirmed several hub genes in three clusters of MI. To lucubrate the potential functions, we performed a ClueGO analysis of these hub networks.Results: In this study, we identified that the levels of FTO, YTHDF3, ZC3H13, and WTAP were dramatically differently expressed in MI tissues compared with controls. Bioinformatics analysis showed that DEGs in MI were significantly related to modulating calcium signaling and chemokine signaling, and m6A regulators were related to regulating glucose measurement and elevated blood glucose levels. Furthermore, genome-wide association study data analysis showed that WTAP single-nucleotide polymorphism was significantly related to the progression of MI. In addition, single-cell sequencing found that WTAP is widely expressed in the heart tissues. Moreover, we conducted consensus clustering for MI in view of the dysregulated m6A regulators’ expression in MI. According to the expression levels, we found MI patients could be clustered into three subtypes. Pathway analysis showed the DEGs among different clusters in MI were assigned to HIF-1, IL-17, MAPK, PI3K-Akt signaling pathways, etc. The module analysis detected several genes, including BAG2, BAG3, MMP2, etc. We also found that MI-related network was significantly related to positive and negative regulation of angiogenesis and response to heat. The hub networks in MI clusters were significantly related to antigen processing and ubiquitin-mediated proteolysis, RNA splicing, and stability, indicating that these processes may contribute to the development of MI.Conclusion: Collectively, our study could provide more information for understanding the roles of m6A in MI, which may provide a novel insight into identifying biomarkers for MI treatment and diagnosis.

Diagnosis, clustering, and immune cell infiltration analysis of m6A-related genes in patients with acute myocardial infarction—a bioinformatics analysis

“…The calibration and DCA plots also showed the very good fit of the model. Similar to previous findings (18,28), the model showed that methylation was an important molecular change in the development of AMI. Under the model, the 5 most important genes were FTO, WTAP, YTHDC1, IGFBP3, and CBLL1.…”

“…A previous study found that m6A methylation is widely involved in the development of various types of cardiovascular diseases and plays an important regulatory role in heart failure, myocardial hypertrophy, atherosclerosis, and ischemic cardiomyopathy (17). m6A modification, as a pivotal regulator of messenger RNA stability, protein expression, and cellular processes, exhibits important roles in the development of cardiac remodeling and cardiomyocyte contractile function (18). AMI leads to cell death, which promotes the immune inflammatory response.…”

N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization

“…Other reports also demonstrated that cytoplasmic YTHDF3 promotes mRNA translation in synergy with YTHDF1 , meanwhile affecting methylated mRNA decay mediated through YTHDF2 and serves as an initiation factor of protein synthesis from circRNAs in human cells ( 44 – 46 ). For the potential roles of YTHDF3 in cardiovascular diseases, genome-wide association studies (GWAS) showed that SNP rs4739066 on YTHDF3 is significantly associated with myocardial infarction (MI) and Shi et al also found that YTHDF3 is dramatically differentially expressed in MI tissues compared with normal controls ( 47 , 48 ).…”

Progress of Single-Cell RNA Sequencing Technology in Myocardial Infarction Research

“…In this manner, studies have shown that the Ckap4 marker was specifically induced in activated fibroblasts ( 34 ), and exclusive Ddah1 expression in myofibroblasts during MI healing ( 22 ) which may indicate novel activated fibroblast markers. Recently, Shi et al ( 56 ) found the expression levels of FTO (fat mass and obesity-associated protein), YTHDF3 (YTH domain-containing protein 3), ZC3H13 (a zinc finger protein), and WTAP (Wilms' tumor 1-associating protein) were significantly different in myocardial infarction tissues, demonstrating the key role of N6-methyladenosine (m6A) regulator in myocardial infarction. WTAP was significantly reduced in the MI group, and maintaining the normal expression of WTAP may be a preventive or ameliorative means for the treatment of MI.…”