4.8 Article

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

Journal

ELIFE
Volume 2, Issue -, Pages -

Publisher

ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.01323

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Funding

  1. National Science Foundation
  2. National Institutes of Health [U01 HL100406, U01 HL098179, R01 HL057181, P01 HL089707]
  3. American Heart Association
  4. Amyotrophic Lateral Sclerosis Association
  5. California Institute for Regenerative Medicine
  6. William Younger Family Foundation
  7. LK Whittier Foundation
  8. Roddenberry Foundation

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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.

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