Project Summary Heart failure currently drives a significant proportion of health and economic burden in the United States. Although steps have been made in developing effective treatments, the incidence, morbidity, and mortality of heart failure continues to rise. Thus, it is important to seek out new, more effective therapeutics through the study of molecular mechanisms responsible for cardiac dysfunction. Maladaptive cardiac remodeling is driven by changes in gene expression and protein synthesis in cardiomyocytes. How post-transcriptional modifications control the outcome of gene expression to regulate the synthesis of specific proteins in the heart is unclear. We found that METTL3, the methylase responsible for m6A formation on mRNAs, is a critical regulator of cardiac hypertrophy and is essential for the maintenance of cardiac homeostasis. However, the mechanisms through which METTL3 impacts remodeling has yet to be fully understood. In this proposal we examine the role of METTL3-dependent methylation in regulating mRNA translation for maintenance of heart function at baseline and in adaptation to stress. Utilizing METTL3 gain- and loss-of-function mouse models, we aim to uncover the mechanisms through which METTL3 regulates hypertrophic heart remodeling. Considering the critical importance of this enzyme in the heart we will also address the mechanisms regulating its function and specificity. These findings will further our understanding on how post-transcriptional modifications control cardiac gene expression, while also uncovering new targetable pathways for therapeutic development.