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 result...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2013-11-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/01323 |
| _version_ | 1797997565745037312 |
|---|---|
| author | Amy Heidersbach Chris Saxby Karen Carver-Moore Yu Huang Yen-Sin Ang Pieter J de Jong Kathryn N Ivey Deepak Srivastava |
| author_facet | Amy Heidersbach Chris Saxby Karen Carver-Moore Yu Huang Yen-Sin Ang Pieter J de Jong Kathryn N Ivey Deepak Srivastava |
| author_sort | Amy Heidersbach |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:34:40Z |
| format | Article |
| id | doaj.art-7e574b2d00aa47e2b8ec607b379d5148 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:34:40Z |
| publishDate | 2013-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7e574b2d00aa47e2b8ec607b379d51482022-12-22T04:29:20ZengeLife Sciences Publications LtdeLife2050-084X2013-11-01210.7554/eLife.01323microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heartAmy Heidersbach0Chris Saxby1Karen Carver-Moore2Yu Huang3Yen-Sin Ang4Pieter J de Jong5Kathryn N Ivey6Deepak Srivastava7Gladstone 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 StatesGladstone Institute of Cardiovascular Disease, San Francisco, United StatesGladstone Institute of Cardiovascular Disease, San Francisco, United StatesGladstone Institute of Cardiovascular Disease, San Francisco, United StatesGladstone 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 StatesChildren’s Hospital Oakland Research Institute, Oakland, United StatesGladstone Institute of Cardiovascular Disease, San Francisco, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United StatesGladstone 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 StatesmicroRNA-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.https://elifesciences.org/articles/01323microRNA-1cardiacsarcomereTelokinMyocardinsmooth muscle gene expression |
| spellingShingle | Amy Heidersbach Chris Saxby Karen Carver-Moore Yu Huang Yen-Sin Ang Pieter J de Jong Kathryn N Ivey Deepak Srivastava microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart eLife microRNA-1 cardiac sarcomere Telokin Myocardin smooth muscle gene expression |
| title | microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart |
| title_full | microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart |
| title_fullStr | microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart |
| title_full_unstemmed | microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart |
| title_short | microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart |
| title_sort | microrna 1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart |
| topic | microRNA-1 cardiac sarcomere Telokin Myocardin smooth muscle gene expression |
| url | https://elifesciences.org/articles/01323 |
| work_keys_str_mv | AT amyheidersbach microrna1regulatessarcomereformationandsuppressessmoothmusclegeneexpressioninthemammalianheart AT chrissaxby microrna1regulatessarcomereformationandsuppressessmoothmusclegeneexpressioninthemammalianheart AT karencarvermoore microrna1regulatessarcomereformationandsuppressessmoothmusclegeneexpressioninthemammalianheart AT yuhuang microrna1regulatessarcomereformationandsuppressessmoothmusclegeneexpressioninthemammalianheart AT yensinang microrna1regulatessarcomereformationandsuppressessmoothmusclegeneexpressioninthemammalianheart AT pieterjdejong microrna1regulatessarcomereformationandsuppressessmoothmusclegeneexpressioninthemammalianheart AT kathrynnivey microrna1regulatessarcomereformationandsuppressessmoothmusclegeneexpressioninthemammalianheart AT deepaksrivastava microrna1regulatessarcomereformationandsuppressessmoothmusclegeneexpressioninthemammalianheart |