The transcriptional co-repressor TLE3 regulates myogenic differentiation by repressing the activity of the MyoD transcription factor [Gene Regulation]

Satellite cells are skeletal muscle stem cells that provide myonuclei for postnatal muscle growth, maintenance, and repair/regeneration in adults. Normally, satellite cells are mitotically quiescent, but they are activated in response to muscle injury, in which case they proliferate extensively and exhibit upregulated expression of the transcription factor MyoD, a master regulator of myogenesis. MyoD forms a heterodimer with E proteins through their basic helix-loophelix (bHLH) domain, binds to E boxes in the genome, and thereby activates transcription at muscle-specific promoters. MyoD's central role in muscle differentiation has increased interest in finding potential MyoD regulators. Here, we identified transducin-like enhancer of split (TLE3), one of the Groucho/TLE family members, as a regulator of MyoD function during myogenesis. TLE3 was expressed in activated and proliferative satellite cells in which increased TLE3 levels suppressed myogenic differentiation and, conversely, reduced TLE3 levels promoted myogenesis with a concomitant increase in proliferation. We found that, via its Q and SP domains, TLE3 interferes with MyoD function by disrupting the association between the bHLH domain of MyoD and E proteins. Our findings indicate that TLE3 participates in skeletal muscle homeostasis by dampening satellite cell differentiation via repression of MyoD transcriptional activity.

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