Post-transcriptional regulation of cardiac hypertrophy

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.

Grant Number: 5R01HL136951-09
NIH Institute/Center: NIH
Principal Investigator: Federica Accornero