SETDB1 modulates the TGFβ response in Duchenne muscular dystrophy myotubes

Abstract

SUMMARYOveractivation of the TGFβ signaling in Duchenne muscular dystrophy (DMD) is a major hallmark of disease progression, leading to fibrosis and muscle dysfunction. Here, we investigated the role of SETDB1, a histone lysine methyltransferase involved in muscle differentiation. Our data show that, following TGFβ induction, SETDB1 accumulates in the nuclei of healthy myotubes, while being already present in the nuclei of DMD myotubes where TGFβ signaling is constitutively activated. Interestingly, transcriptomics revealed that depletion of SETDB1 in DMD myotubes leads to downregulation of TGFβ-target genes coding for secreted factors involved in extracellular matrix remodeling and inflammation. Consequently, SETDB1 silencing in DMD myotubes abrogates the deleterious effect of their secretome on myoblast differentiation by impairing myoblast pro-fibrotic response. Our findings indicate that SETDB1 potentiates the TGFβ-driven fibrotic response in DMD muscles, providing a new axis for therapeutic intervention.Key resultsTGFβ induces nuclear accumulation of SETDB1 in healthy myotubesSETDB1 is enriched in DMD myotube nuclei with intrinsic TGFβ pathway overactivationSETDB1 LOF in DMD myotubes attenuates TGFβ-induced pro-fibrotic responseSecretome of TGFβ-treated DMD myotubes with SETDB1 LOF is less deleterious on myoblast differentiation