Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA

Maternal loss of imprinting (LOI) at the locus results in biallelic and reduced expression and is associated with Beckwith--Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of and mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased . Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These -dependent phenotypes are transient: cardiac size returns to normal once expression is suppressed postnatally. However, reduced expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, expression is primarily in endothelial cells (ECs) and regulates EC differentiation both in vivo and in vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend on lncRNA interactions with microRNAs.