Abstract 944: Differential Dna Methylation Co-segregates With the Severity of Heart Failure

Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. As a potential epigenetic biomarker, DNA methylation differs between healthy and diseased hearts. However, its association according to disease severity has not yet been studied. Here, we sought to investigate how DNA methylation (DNAm) differs across HF disease severity, and study the use of a DNMT methyltransferase inhibitor RG108 on DNAm and its effect on heart function. A fixed dose of Isoprenaline (ISO), or saline control (SAL), administered to a hybrid mouse diversity panel (HMDP) consisting of 85 classical and recombinant inbred mouse strains produced a range of cardiac hypertrophy and/or LV dilatation. Left ventricles were harvested and subjected to genome-wide cardiac DNAm profiling by Reduced Representation Bisulfite Sequencing (RRBS). Unsupervised clustering of the top 1% most variable CpG methylation segregated strains to their genetic origin. Disregarding strain-specific methylation differences, differential methylation between ISO and SAL unexpectedly categorised mice into mild and severe disease responders. In the severe-responder strain BTBRT, the pharmacological DNMT methyltransferase inhibitor, RG108, rescued disease from ISO-response, with accompanying evidence of gene expression recovery. This work establishes the range of cardiac differential DNAm correlating according to disease severity. It displays the involvement of DNA methylation-dependent gene expression changes that turns out to be unique, despite different mouse strain backgrounds. This gives further proof of principle that cardiac DNAm changes represent novel biomarkers for disease stratification and consequent targeted therapy.