Multi-omic profiling of cardiomyocyte ageing and functional decline

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Molecular Gerontology

Background:

• Ageing is the primary risk factor for heart failure.
• Molecular mechanisms of cardiomyocyte ageing are not fully understood.

Purpose of the Study:

• Map the transcriptomic and epigenomic landscape of cardiomyocyte ageing.
• Investigate if DNA hypermethylation causally drives diastolic dysfunction.

Main Methods:

• Single-nucleus multiomics (snRNA-seq and snATAC-seq) on mouse ventricular myocardium.
• Reduced-representation bisulphite sequencing to assess DNA methylation.
• Adeno-associated virus (AAV) mediated overexpression of Dnmt3a in adult mouse hearts.

Main Results:

• Aged cardiomyocytes exhibit widespread chromatin remodelling and increased DNA hypermethylation.
• DNA hypermethylation inversely correlated with differential gene expression.
• Dnmt3a overexpression induced hypermethylation, cardiac hypertrophy, and diastolic dysfunction, mimicking ageing phenotypes.

Conclusions:

• Chromatin accessibility gain and CpG hypermethylation characterize cardiomyocyte ageing.
• DNMT3A-mediated hypermethylation is a mechanistic driver of age-related cardiac dysfunction.
• Targeting DNA methylation may offer therapeutic strategies for age-related cardiac dysfunction.