Multifaceted roles of miR-1s in repressing the fetal gene program in the heart.
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.
1] Mindich Child Health and Development Institute, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1040, New York, NY 10029, USA [2] Current address: College of Life Sciences, Peking University, Beijing 100871, China.
Yusheng
Y
Wei
Mindich Child Health and Development Institute, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1040, New York, NY 10029, USA.
Siwu
S
Peng
Mindich Child Health and Development Institute, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1040, New York, NY 10029, USA.
Meng
M
Wu
Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Ravi
R
Sachidanandam
Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Zhidong
Z
Tu
Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Shihong
S
Zhang
Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Christine
C
Falce
Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Eric A
EA
Sobie
Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Djamel
D
Lebeche
Mindich Child Health and Development Institute, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1040, New York, NY 10029, USA.
Yong
Y
Zhao
D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000235:genetics / Q000401:mortality; D049109:Cell Proliferation; D002478:Cells, Cultured; D004734:Energy Metabolism; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D016415:Sequence Alignment
D020413:3' Untranslated Regions; D035683:MicroRNAs; D011960:Receptors, Estrogen; C107914:estrogen receptor-related receptor beta; D006003:Glycogen