VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle

VGLL proteins are transcriptional co-factors that bind TEAD family transcription factors to regulate events ranging from wing development in fly, to muscle fibre composition and immune function in mice. Here, we characterise Vgll3 in skeletal muscle. Vgll3 is expressed at low levels in healthy muscle but levels increase during hypertrophy or regeneration, and in disease, VGLL3 is highly expressed in dystrophic muscle and alveolar rhabdomyosarcoma. Interaction proteomics revealed that VGLL3 binds TEAD1,3,4 in myoblasts and/or myotubes. However, there is no interaction with proteins of major regulatory systems such as the Hippo kinase cascade, unlike the TEAD cofactors YAP and TAZ. Vgll3 overexpression reduces the Hippo negative feedback loop, affecting expression of muscle-regulating genes including Myf5, Pitx2/3, Wnts and IGFBP. Vgll3 mainly represses gene expression, regulating similar genes to that of YAP1 and TAZ. SiRNA-mediated Vgll3 knockdown suppresses myoblast proliferation, while Vgll3 overexpression strongly promotes myogenic differentiation. Skeletal muscle is overtly normal in Vgll3-null mice though, presumably due to feedback signalling and/or redundancy. This work identifies Vgll3 as a transcriptional cofactor operating with the Hippo signal transduction network to control myogenesis.