GSE111418
Mis-expression of Igf2 and H19 work independently on distinct cell types to cause cardiomyopathy in a Beckwtih Wiedemann mouse model
Igf2 and H19 are linked, reciprocally imprinted genes that play critical roles in mammalian development.  Igf2 encodes a peptide hormone, Insulin-like Growth Factor 2, that binds to the InsR and Igf1R receptor kinases to regulate cell growth and metabolism through well-established pathways.  H19 encodes a 2.3 kb lncRNA whose biochemical actions are only now being identified.  Here we use a mouse model to investigate cardiomyopathies associated with maternal loss of imprinting at the locus.  Increased circulating levels of IGF2 during fetal development result in activation of pAKT/mTOR signaling in cardiomyocytes to cause cellular hypertrophy and hyperplasia in neonatal hearts. This neonatal hypertrophy is unaffected by H19 RNA levels.  However, loss of H19 does cause fibrosis and progressive cardiac pathology in adult mice.  In hearts, H19 expression is concentrated in endothelial cells associated with blood vessels and capillaries and loss of H19 results in high incidence of trans differentiation of these cells to smooth muscle.  H19 encoded miRNAs 675-3p and -5p are not sufficient to promote normal development. Thus these experiments define a novel role for the H19 lncRNA in regulating cell fate. Overall design: Total of 4 samples: RNA-Seq from 2 genotypes: wild-type and dICR/dICR. Tissue analyzed is heart from 6 month-old mice.