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miRNAs Influence m6A RNA Methylation through FTO and IGF2BP2 in Pressure Overload-Induced Heart Failure
Yuanqi Wang1, Linghao Xu1, Md Sakibur Rahman Tapu1
1Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Background:
N6-adenosine methylation (m6A) is a prevalent RNA modification associated with heart failure, alongside aberrant miRNA expression. Despite indications of miRNAs regulating m6A modification, their specific influence on m6A in heart failure remains unclear.
Methods:
The initial analysis utilized transcriptome and methylation sequencing data from GSE131296 in mice to identify key m6A methylation enzymes in heart failure and construct an associated network. Integration of miRNA sequencing data from GSE231700 revealed miRNAs influencing m6A methylation enzymes, contributing to the formation of a comprehensive network. Furthermore, differential miRNA levels in human serum were assessed via qPCR, and the expression of m6A methyltransferases in the heart was confirmed using proteomic databases.
Results:
In pressure overload-induced heart failure mice, 217 mRNAs showed differential expression, with FTO and IGF2BP2 identified as m6A methylation enzymes. Subsequent methylation sequencing revealed 884 highly-methylated and 178 lowly-methylated peaks, establishing a network linking Fto and Igf2bp2 with these peaks. Additionally, miRNA sequencing identified 156 differentially expressed miRNAs, including let-7b-5p and miR-23b-3p, predicted as m6Aregulating miRNAs, both elevated in heart failure patients.
Conclusion:
miR-23b-3p and let-7b-5p are identified as potential regulators of RNA methylation in heart failure, acting via FTO and IGF2BP2, offering new insights into the role of miRNA- mediated RNA methylation and its potential therapeutic avenues for heart failure.
Insights
MicroRNAs miR-23b-3p and let-7b-5p regulate RNA methylation via FTO and IGF2BP2 in heart failure. This discovery offers new therapeutic strategies for heart failure patients.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Molecular Biology
Background:
- N6-adenosine methylation (m6A) is a key RNA modification linked to heart failure.
- Aberrant microRNA (miRNA) expression also characterizes heart failure.
- The precise role of miRNAs in regulating m6A during heart failure is not well understood.
Purpose of the Study:
- To investigate the influence of miRNAs on m6A methylation enzymes in the context of heart failure.
- To construct a regulatory network connecting miRNAs, m6A enzymes, and RNA methylation in heart failure.
Main Methods:
- Transcriptome and m6A methylation sequencing data from mouse models of heart failure (GSE131296).
- Integration of miRNA sequencing data (GSE231700) to identify miRNA regulators.
- Quantitative PCR (qPCR) for human serum miRNA analysis and proteomic database confirmation of m6A methyltransferases.
Main Results:
- Identified FTO and IGF2BP2 as key m6A methylation enzymes in heart failure.
- Revealed 884 highly-methylated and 178 lowly-methylated RNA peaks associated with FTO and IGF2BP2.
- Discovered 156 differentially expressed miRNAs, including elevated let-7b-5p and miR-23b-3p in heart failure patients.
Conclusions:
- miR-23b-3p and let-7b-5p are identified as potential regulators of RNA methylation in heart failure.
- These miRNAs likely act through the m6A enzymes FTO and IGF2BP2.
- Findings provide novel insights into miRNA-mediated RNA methylation in heart failure and suggest potential therapeutic targets.
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