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Nat Genet. 2015 Jul;47(7):776-83. doi: 10.1038/ng.3324. Epub 2015 Jun 1.

Trbp regulates heart function through microRNA-mediated Sox6 repression.

Author information

1
Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
Departmant of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
3
1] Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
4
1] Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] College of Life Sciences, Hubei University, Wuhan, China.
5
1] Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
6
Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
7
1] Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.

Abstract

Cardiomyopathy is associated with altered expression of genes encoding contractile proteins. Here we show that Trbp (Tarbp2), an RNA-binding protein, is required for normal heart function. Cardiac-specific inactivation in mice of Trbp (Trbp(cKO)) caused progressive cardiomyopathy and lethal heart failure. Loss of Trbp function resulted in upregulation of Sox6, repression of genes encoding normal cardiac slow-twitch myofiber proteins and pathologically increased expression of genes encoding skeletal fast-twitch myofiber proteins. Remarkably, knockdown of Sox6 fully rescued the Trbp-mutant phenotype, whereas mice overexpressing Sox6 phenocopied Trbp(cKO) mice. Trbp inactivation was mechanistically linked to Sox6 upregulation through altered processing of miR-208a, which is a direct inhibitor of Sox6. Transgenic overexpression of Mir208a sufficiently repressed Sox6, restored the balance in gene expression for fast- and slow-twitch myofiber proteins, and rescued cardiac function in Trbp(cKO) mice. Together, our studies identify a new Trbp-mediated microRNA-processing mechanism in the regulation of a linear genetic cascade essential for normal heart function.

PMID:
26029872
PMCID:
PMC4485565
DOI:
10.1038/ng.3324
[Indexed for MEDLINE]
Free PMC Article

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