Abstract 17407: Modulation of N6-Methyladenosine (m6A) by the Fat Mass Obesity-Associated Gene (FTO) Regulates Cardiac Function

Introduction: Protein expression in the left ventricle of a failing human heart does not correlate with the corresponding mRNA abundance, suggesting a major role for post-transcriptional (epitranscriptomic) modifications. A series of recent publications suggest that the most abundant and functionally relevant chemical modification in RNA, N6-methyladenosine (m6A) is a critical regulator of protein expression. While dysregulated m6A has been linked to various types of cancer and brain diseases, its role in cardiac function and heart failure has not been studied. Objective: In a first-of-its-kind study, we propose to examine the role of cardiac m6A-epitranscriptome in the pathomechanisms of heart failure at the molecular (protein expression), cellular and tissue (cardiomyocyte and cardiac function) level. Methods and Results: We discovered that m6A is significantly higher in failing human and mouse hearts and is associated with lower expression of FTO, an m6A eraser. Similarly, hypoxia-induced m6A correlate...