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

Abstract

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 β (Errβ) was identified as a direct target of miR-1, which can regulate glycolysis, glycogenesis, and the expression of sarcomeric proteins. Cardiac-specific overexpression of Errβ 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 Errβ 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.

• Authors: Yusheng Wei, Siwu Peng, Meng Wu, Ravi Sachidanandam, Zhidong Tu, Shihong Zhang, Christine Falce, Eric A Sobie, Djamel Lebeche, Yong Zhao
• Journal: Cell research (Cell Res) Vol. 24 Issue 3 Pg. 278-92 (Mar 2014) ISSN: 1748-7838 [Electronic] England
• PMID: 24481529 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• MicroRNAs
• Receptors, Estrogen
• estrogen receptor-related receptor beta
• Glycogen

Topics

• 3' Untranslated Regions
• Animals
• Base Sequence
• Cardiomyopathy, Dilated (etiology, genetics, mortality)
• Cell Proliferation
• Cells, Cultured
• Energy Metabolism
• Glycogen (metabolism)
• Glycolysis
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• MicroRNAs (antagonists & inhibitors, metabolism)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (cytology, metabolism)
• Receptors, Estrogen (antagonists & inhibitors, genetics, metabolism)
• Sarcomeres (metabolism)
• Sequence Alignment