Trbp regulates heart function through microRNA-mediated Sox6 repression

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies / genetics
  • Cardiomyopathies / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Myocardium / metabolism*
  • RNA Interference
  • RNA-Binding Proteins / physiology*
  • SOXD Transcription Factors / genetics*
  • SOXD Transcription Factors / metabolism
  • Transcriptome


  • MicroRNAs
  • Mirn208 microRNA, mouse
  • RNA-Binding Proteins
  • SOXD Transcription Factors
  • Sox6 protein, mouse
  • trans-activation responsive RNA-binding protein

Associated data

  • GEO/GSE67658