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

Maternal loss of imprinting (LOI) at theH19/IGF2locus results in biallelicIGF2and reducedH19expression and is associated with Beckwith Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance ofIgf2andH19mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increasedIgf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. TheseIgf2-dependent phenotypes are transient: cardiac size returns to normal onceIgf2expression is suppressed postnatally. However, reducedH19expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart,H19expression is concentrated predominantly in endothelial cells (ECs) and regulates EC differentiation both,in vivoandin vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend onH19lncRNA interactions withlet7microRNA.