SETDB1 modulates the TGFβ response in Duchenne muscular dystrophy myotubes
Year: 2024
Type: article
Abstract: Overactivation of the transforming growth factor-β (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 (SET domain, bifurcated 1), 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. Transcriptomics revealed that depletion of SETDB1 in DMD myotubes leads to down-regulation 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 an additional axis for therapeutic intervention.
Source: Science Advances
Institutions: Centre National de la Recherche Scientifique, Université Paris Cité, Epigénétique et Destin Cellulaire, Inserm, Sorbonne Université, Institut de Myologie, Centre de Recherche en Myologie, Lyon 1 Université, Institut NeuroMyoGène, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: Determinants de l'Identité : de la molécule à l'individu, Signaling and epigenetics during skeletal muscle differentiation: Regulation of histone and non-histone lysine methylation by the Wnt pathway, Epigenetic Regulation of Secretome in Duchenne Muscular Dystrophy: role of the Histone Methyltransferase SETDB1 in TGFbeta-induced Fibrosis, G4774453313, G4866930200, G5013758650, G6803667113, G7351676700, A multidimensional single-cell approach to understand muscle dystrophy, Université Sorbonne Paris Cité
OpenAlex ID: W4396541920