MyoD transcription factor induces myogenesis by inhibiting Twist-1 through miR-206

Abstract

Twist-1 is mostly expressed during development and has been previously shown to control myogenesis. Since its regulation in muscle has not been fully exploited, the aim of the project was to identify miRNAs in muscle which regulate Twist-1. miR-206, one of the most important myomiRs, was identified as a possible candidate for Twist-1 mRNA. Luciferase assays and transfections in human foetal myoblasts showed that Twist-1 is a direct target for miR-206 and through this pathway muscle cell differentiation is promoted. We next investigated whether MyoD, a major myogenic transcription factor regulates Twist-1, since it is known that MyoD induces miR-206 gene expression. We found that forced MyoD expression induces miR-206 up-regulation and Twist-1 down-regulation through miR-206 promoter binding, followed by increase in muscle cell differentiation. Finally, experiments were performed in muscle cells from patients with congenital Myotonic Dystrophy type 1 which fail to differentiate to myotubes. MyoD overexpression inhibited Twist-1 through miR-206 induction, followed by an increase in muscle cell differentiation. These results reveal a novel mechanism of myogenesis which might also play an important role in muscle disease.