microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart

Elife. 2013 Nov 19;2:e01323. doi: 10.7554/eLife.01323.

Abstract

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 by regulating both transcriptional and effector nodes of the smooth muscle gene expression network. DOI: http://dx.doi.org/10.7554/eLife.01323.001.

Keywords: Myocardin; Telokin; cardiac; microRNA-1; sarcomere; smooth muscle gene expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression*
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Muscle, Smooth / metabolism*
  • Myocardium / metabolism*
  • Phosphorylation
  • Sarcomeres*

Substances

  • MIRN1 microRNA, human
  • MicroRNAs