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Multifaceted roles of miR-1s in repressing the fetal gene program in the heart.

Authors: Wei, Yusheng  Peng, Siwu  Wu, Meng  Sachidanandam, Ravi  Tu, Zhidong  Zhang, Shihong  Falce, Christine  Sobie, Eric A  Lebeche, Djamel  Zhao, Yong 
Citation: Wei Y, etal., Cell Res. 2014 Mar;24(3):278-92. doi: 10.1038/cr.2014.12. Epub 2014 Jan 31.
Pubmed: (View Article at PubMed) PMID:24481529
DOI: Full-text: DOI:10.1038/cr.2014.12

miRNAs are an important class of regulators that play roles in cellular homeostasis and disease. Muscle-specific miRNAs, miR-1-1 and miR-1-2, have been found to play important roles in regulating cell proliferation and cardiac function. Redundancy between miR-1-1 and miR-1-2 has previously impeded a full understanding of their roles in vivo. To determine how miR-1s regulate cardiac function in vivo, we generated mice lacking miR-1-1 and miR-1-2 without affecting nearby genes. miR-1 double knockout (miR-1 dKO) mice were viable and not significantly different from wild-type controls at postnatal day 2.5. Thereafter, all miR-1 dKO mice developed dilated cardiomyopathy (DCM) and died before P17. Massively parallel sequencing showed that a large portion of upregulated genes after deletion of miR-1s is associated with the cardiac fetal gene program including cell proliferation, glycolysis, glycogenesis, and fetal sarcomere-associated genes. Consistent with gene profiling, glycogen content and glycolytic rates were significantly increased in miR-1 dKO mice. Estrogen-related Receptor ß (Errß) was identified as a direct target of miR-1, which can regulate glycolysis, glycogenesis, and the expression of sarcomeric proteins. Cardiac-specific overexpression of Errß led to glycogen storage, cardiac dilation, and sudden cardiac death around 3-4 weeks of age. We conclude that miR-1 and its primary target Errß act together to regulate the transition from prenatal to neonatal stages by repressing the cardiac fetal gene program. Loss of this regulation leads to a neonatal DCM.

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RGD Object Information
RGD ID: 12910990
Created: 2017-07-05
Species: All species
Last Modified: 2017-07-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.