Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.06.28.546840v1?rss=1

Authors: Ait-Si-Ali, S., Granados, A., Zamperoni, M., Rapone, R., Bouyioukos, C., Del Maestro, L., Joliot, V., Albini, S.

Abstract:
The histone lysine methyltransferase SETDB1 is involved in muscle differentiation and has been shown as a regulator of the TGF{beta} pathway in cancer contexts. Here, we investigated the role of SETDB1 in Duchenne muscular dystrophy (DMD) myotubes harboring an overactivated TGFbeta pathway. Our data show that challenging healthy myotubes with TGFbeta induces nuclear accumulation of SETDB1, while in DMD myotubes SETDB1 is constantly accumulated in nuclei in TGFbeta-dependent fashion. SETDB1 loss-of-function (LOF) leads to a decrease of the TGFbeta downstream target genes in DMD myotubes, suggesting the involvement of a TGFbeta/SETDB1 axis in DMD physiopathology. Transcriptomics show that many targets of SETDB1 code for secreted factors involved in fibrosis, extracellular matrix remodeling and inflammation and are downregulated when SETDB1 is silenced. Conditioned medium assays show that SETDB1 LOF in DMD myotubes abrogates the deleterious effect of the secretome on myoblast differentiation and impairs their pro-fibrotic response. Together, our findings indicate that SETDB1 potentiates the TGFbeta response in DMD muscles and participates in fibrosis.

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