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Comprehensive Analysis of N6-Methyladenosine (m6A) Methylation in human Calcific Aortic Valve Tissues by High-Throughput m6A Sequencing

ABSTRACT: Background: Recent research shows cardiovascular diseases have been strongly linked to N6-methyladenosine (m6A) methylation. However, there is still much to learn about the specific changes in m6A RNA methylation in patients with calcified aortic valve dBackground: Recent research shows cardiovascular diseases have been strongly linked to N6-methyladenosine (m6A) methylation. However, there is still much to learn about the specific changes in m6A RNA methylation in patients with calcified aortic valve disease (CAVD). Methods: In this study, high-throughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were performed to identify the differentially expressed m6A methylation pattern in human calcified valves tissue for the first time. Results: A total of 7,412 significantly changed m6A methylation peaks and 2,380 differentially expressed genes were identified. MeRIP-seq and RNA-seq analyses screened out 131 genes with significant m6A methylation and expression changes. Gene Ontology (GO) analysis also revealed a relationship between m6A methylated genes and inflammatory responses, calcium ion binding, extracellular matrix organization, and cell adhesion, among other. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these genes had an increased role in focal adhesion. Using real-time qPCR, we also confirmed the presence of 4 genes involving the focal adhesion signaling pathway (SPP1, COL1A1, ITGA8, and MYL9). Conclusions: Taken together, our study firstly revealed the distinct m6A methylation profiles in calcified valve tissue and associated biological roles and signaling pathways. The information in this study will be useful for future mechanism research and for developing new treatment targets for patients with CAVD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227247 | GEO | 2023/03/16

REPOSITORIES: GEO

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Project description:Aims Calcific aortic valve disease (CAVD) is a significant cause of illness and death worldwide. The disease mechanism involves age-associated immuno-osteogenic processes but developmental origins and early disease mechanisms are not fully characterized. Identification of early predictive markers could help optimize therapy decisions and patient follow-up. Methods and Results RNA-sequencing was carried out on human fetal aortic valves at weeks 9, 13, and 22, and adult control, calcified bicuspid (BAV) and tricuspid aortic valves (TAV). K-means clustering was implemented to identify co-expressed gene patterns simultaneously up- and down-regulated over the different conditions. Canonical pathway analysis revealed a predominant immune-metabolic gene signature indicative of ongoing innate and adaptive immune responses, including lymphocyte T-cell metabolic adaptation. Specifically, cytokine and chemokine signalling, cellular migration and proliferation, were all increased in CAVD, while oxidative phosphorylation and protein translation were decreased. Discrete immune-metabolic gene signatures were present at foetal stages and adult controls, indicating that inflammation initiates as soon as the valves are formed and is maintained and amplified during post-natal life. Multiple pathways involved in cellular stress response and neurodegenerative disease were also aberrantly expressed, suggesting that chronic inflammation drives metabolic stress- and age-associated valve pathology in CAVD. Comparing the valve RNA-sequencing dataset with whole blood transcriptomes from asymptomatic individuals with early aortic valve calcification identified a gene signature including the CD28 pathway, highly predictive of patients with CAVD and healthy individuals with moderate levels of aortic valve calcification. Conclusion These data deepen and broaden our understanding of the molecular basis of CAVD, and identify a gene signature for the early detection of aortic valve calcification. Keywords Human foetal valve, CAVD, BAV, inflammation, biomarker, gene signature,PESA

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Comprehensive Analysis of N6-Methyladenosine (m6A) Methylation in human Calcific Aortic Valve Tissues by High-Throughput m6A Sequencing

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