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

Abstract

Maternal loss of imprinting (LOI) at the <i>H19/IGF2</i> locus results in biallelic <i>IGF2</i> and reduced <i>H19</i> expression and is associated with Beckwith--Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of <i>Igf2</i> and <i>H19</i> mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased <i>Igf2</i>. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These <i>Igf2</i>-dependent phenotypes are transient: cardiac size returns to normal once <i>Igf2</i> expression is suppressed postnatally. However, reduced <i>H19</i> expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, <i>H19</i> 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 <i>H19</i> lncRNA interactions with <i>Mirlet7</i> microRNAs.