Tip60 regulates myoblast differentiation by enhancing the transcriptional activity of MyoD via their physical interactions.

The progression of muscle differentiation is tightly controlled by multiple groups of transcription factors and transcriptional coregulators. MyoD is a transcription factor of the myogenic basic helix-loop-helix family required for the process of muscle cell differentiation. We now show that Tip60 is required for myoblast differentiation via enhancement of the transcriptional activity of MyoD. Knockdown of Tip60 in C2C12 cells leads to a lack of ability to switch from proliferating myoblasts to differentiated myotubes. Ectopic expression of Tip60 increased MyoD-mediated luciferase activity on the myogenic regulatory gene, myogenin. We also found that Tip60 physically interacts with MyoD using its chromo- and Zn-finger-containing region, and that these protein interactions were required for the effective transcriptional activation of MyoD. Furthermore, a chromatin immunoprecipitation assay revealed that Tip60 recruits MyoD on the myogenin promoter, and Tip60 also increases the levels of acetylated histones H3 and H4 during myogenic differentiation. Taken together, these findings suggest that Tip60 is an important co-activator for MyoD-mediated myogenesis in mouse myoblast C2C12 cells.