Transcriptome-wide N6-methyladenosine methylation landscape of coronary artery disease

Area of Science:

• Epigenetics
• Cardiovascular Research
• Molecular Biology

Background:

• Coronary artery disease (CAD) is a leading cause of mortality worldwide.
• The role of RNA modifications, specifically N6-methyladenosine (m⁶A), in CAD pathogenesis is not fully understood.

Purpose of the Study:

• To comprehensively profile the transcriptome-wide m⁶A methylome in CAD.
• To identify differentially methylated sites and genes associated with CAD.
• To investigate the functional role of m⁶A regulators in CAD-related processes.

Main Methods:

• Colorimetric measurement of m⁶A levels in peripheral blood mononuclear cells (PBMCs).
• Methylated RNA immunoprecipitation sequencing (MeRIP-seq) to profile m⁶A methylome across mRNAs and lncRNAs.
• Bioinformatic analysis to identify differentially methylated genes and pathways.
• MeRIP-quantitative real-time PCR (MeRIP-qPCR) for data validation.
• Rat carotid artery balloon injury model to assess the role of FTO in neointima formation.

Main Results:

• Significantly decreased global m⁶A RNA levels were observed in CAD patients compared to controls.
• MeRIP-seq identified numerous differentially methylated m⁶A sites in both mRNAs and lncRNAs between CAD and control groups.
• Bioinformatic analysis linked these differentially methylated genes to pathways involved in atherosclerosis.
• MeRIP-qPCR confirmed the accuracy of MeRIP-seq findings.
• The m⁶A demethylase FTO was implicated in neointima formation in a rat model.

Conclusions:

• This study provides the first transcriptome-wide m⁶A methylome profile in CAD.
• The findings highlight the dysregulation of m⁶A modification in CAD pathogenesis.
• The identified m⁶A profile serves as a valuable resource for understanding m⁶A's biological functions in CAD and developing potential therapeutic strategies.