microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart
Amy Heidersbach,
Chris Saxby,
Karen Carver-Moore,
Yu Huang,
Yen-Sin Ang,
Pieter J de Jong,
Kathryn N Ivey,
Deepak Srivastava
Affiliations
Amy Heidersbach
Gladstone Institute of Cardiovascular Disease, San Francisco, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
Chris Saxby
Gladstone Institute of Cardiovascular Disease, San Francisco, United States
Karen Carver-Moore
Gladstone Institute of Cardiovascular Disease, San Francisco, United States
Yu Huang
Gladstone Institute of Cardiovascular Disease, San Francisco, United States
Yen-Sin Ang
Gladstone Institute of Cardiovascular Disease, San Francisco, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
Pieter J de Jong
Children’s Hospital Oakland Research Institute, Oakland, United States
Kathryn N Ivey
Gladstone Institute of Cardiovascular Disease, San Francisco, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States
Deepak Srivastava
Gladstone Institute of Cardiovascular Disease, San Francisco, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
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.
