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m6A methylation in myocardial tissue of septic mice analyzed using MeRIP/m6A-sequencing and RNA-sequencing
Xue Liang1, Xiaotong Hu1, Jiao Li2
1Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
Abstract:
Septic cardiomyopathy is a secondary myocardial injury caused by sepsis. N6-methyl-adenosine (m6A) modification is involved in the pathological progression of septic cardiomyopathy; however, the pathological mechanism remains unclear. In this study, we identified the overall m6A modification pattern in septic myocardial injury and determined its potential interactions with differentially expressed genes (DEGs). A sepsis mouse model exhibiting septic symptoms and myocardial tissue damage was induced by lipopolysaccharide (LPS). LPS-induced septic myocardial tissues and control myocardial tissues were subjected to methylated RNA immunoprecipitation sequencing and RNA sequencing to screen for differentially expressed m6A peaks and DEGs. We identified 859 significantly m6A-modified genes in septic myocardial tissues, including 432 upregulated and 427 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to explore the biological importance of differentially expressed m6A methylated genes and DEGs. Differentially expressed m6A methylated genes were enriched in immune- and inflammation-related pathways. Conjoint analysis revealed co-expression of differentially expressed m6A genes and DEGs, including genes that were upregulated or downregulated and those showing opposite trends. High expression of m6A-related genes (WTAP and IGF2BP2), interleukin-17, and interleukin-17 pathway-related genes (MAPK11 and TRAF3IP2) was verified using reverse transcription-quantitative PCR. We confirmed the presence of m6A modification of the transcriptome and m6A-mediated gene expression in septic myocardial tissues.
Insights
This study reveals how N6-methyl-adenosine (m6A) modification patterns contribute to septic cardiomyopathy, a heart injury from sepsis. Researchers identified key m6A-modified genes and their interaction with gene expression changes in sepsis-induced heart damage.
Area of Science:
- Molecular Biology
- Cardiology
- Immunology
Background:
- Septic cardiomyopathy is a critical myocardial injury resulting from sepsis.
- The precise pathological mechanisms of septic cardiomyopathy, particularly the role of N6-methyl-adenosine (m6A) modification, remain incompletely understood.
Purpose of the Study:
- To elucidate the m6A modification patterns in septic myocardial injury.
- To investigate the interactions between m6A-modified genes and differentially expressed genes (DEGs) in the context of sepsis.
Main Methods:
- A lipopolysaccharide (LPS)-induced sepsis mouse model was established to mimic septic symptoms and myocardial damage.
- Methylated RNA immunoprecipitation sequencing (m6A-IP-seq) and RNA sequencing (RNA-seq) were employed to identify differentially expressed m6A peaks and DEGs in septic myocardial tissues.
- Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted.
Main Results:
- A total of 859 significantly m6A-modified genes were identified in septic myocardial tissues, with 432 upregulated and 427 downregulated.
- Differentially expressed m6A-modified genes were predominantly enriched in immune and inflammation-related pathways.
- Conjoint analysis demonstrated co-expression between differentially expressed m6A genes and DEGs, including genes with concordant and discordant expression trends.
- High expression of m6A-related genes (WTAP, IGF2BP2) and interleukin-17 pathway genes (MAPK11, TRAF3IP2) was validated.
Conclusions:
- The study successfully characterized the m6A modification landscape in septic myocardial injury.
- m6A modification plays a significant role in the pathogenesis of septic cardiomyopathy, particularly through its influence on immune and inflammatory responses.
- These findings highlight the potential of targeting m6A modification pathways for therapeutic interventions in septic cardiomyopathy.
