Trbp regulates heart function through microRNA-mediated Sox6 repression

Jian Ding, Jinghai Chen, Yanqun Wang, Masaharu Kataoka, Lixin Ma, Pingzhu Zhou, Xiaoyun Hu, Zhiqiang Lin, Mao Nie, Zhong Liang Deng, William T. Pu, Da Zhi Wang

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)776-783
Number of pages8
JournalNature genetics
Volume47
Issue number7
DOIs
Publication statusPublished - 2015 Jun 26

ASJC Scopus subject areas

  • Genetics

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  • Cite this

    Ding, J., Chen, J., Wang, Y., Kataoka, M., Ma, L., Zhou, P., Hu, X., Lin, Z., Nie, M., Deng, Z. L., Pu, W. T., & Wang, D. Z. (2015). Trbp regulates heart function through microRNA-mediated Sox6 repression. Nature genetics, 47(7), 776-783. https://doi.org/10.1038/ng.3324