PRJNA219345
microRNA-1 Regulates Sarcomere Formation and Suppresses Smooth Muscle Gene Expression in the Mammalian Heart
microRNA-1 (miR-1) is an evolutionarily conserved, striated muscle enriched miRNA. Most mammalian genomes contain two copies of miR-1 and in mice, deletion of a single locus, miR-1-2, causes incompletely penetrant lethality and subtle cardiac defects. Here, we report that deletion of miR-1-1 resulted in a phenotype similar to that of the miR-1-2 mutant. Compound miR-1 knockout mice died uniformly before weaning due to severe cardiac dysfunction. miR-1-null cardiomyocytes had abnormal sarcomere organization and decreased phosphorylation of the regulatory myosin light chain-2 (MLC2), a critical cytoskeletal regulator. The smooth muscle restricted inhibitor of MLC2 phosphorylation, Telokin, was ectopically expressed in the myocardium, along with other smooth-muscle genes. miR-1 repressed Telokin expression through direct targeting and by repressing its transcriptional regulator, Myocardin. Our results reveal that miR-1 is required for postnatal cardiac function and reinforces the striated muscle phenotype through regulation of both transcriptional and effector nodes of the smooth-muscle gene-expression network.