| First Author | Ding J | Year | 2015 |
| Journal | Nat Genet | Volume | 47 |
| Issue | 7 | Pages | 776-83 |
| PubMed ID | 26029872 | Mgi Jnum | J:222613 |
| Mgi Id | MGI:5644972 | Doi | 10.1038/ng.3324 |
| Citation | Ding J, et al. (2015) Trbp regulates heart function through microRNA-mediated Sox6 repression. Nat Genet 47(7):776-83 |
| abstractText | 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. |
