Journal
FASEB JOURNAL
Volume 36, Issue 7, Pages -Publisher
WILEY
DOI: 10.1096/fj.202200215R
Keywords
E box; endoplasmic reticulum stress; gene silencing; microarray analysis; muscle regeneration; myoblast differentiation; promoter; skeletal muscle; transcription
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Funding
- Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR)
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This study reveals that SNAI1 is upregulated during early muscle regeneration and acts as a direct repressor of ER stress and Fgf21 expression. The findings provide insights into the regulatory mechanism of myogenic differentiation and the maintenance of undifferentiated state in myoblasts.
During skeletal myogenesis, the zinc-finger transcription factors SNAI1 and SNAI2, are expressed in proliferating myoblasts and regulate the transition to terminally differentiated myotubes while repressing pro-differentiation genes. Here, we demonstrate that SNAI1 is upregulated in vivo during the early phase of muscle regeneration induced by bupivacaine injury. Using shRNA-mediated gene silencing in C2C12 myoblasts and whole-transcriptome microarray analysis, we identified a collection of genes belonging to the endoplasmic reticulum (ER) stress pathway whose expression, induced by myogenic differentiation, was upregulated in absence of SNAI1. Among these, key ER stress genes, such as Atf3, Ddit3/Chop, Hspa5/Bip, and Fgf21, a myokine involved in muscle differentiation, were strongly upregulated. Furthermore, by promoter mutant analysis and Chromatin immune precipitation assay, we demonstrated that SNAI1 represses Fgf21 and Atf3 in proliferating myoblasts by directly binding to multiple E boxes in their respective promoter regions. Together, these data describe a new regulatory mechanism of myogenic differentiation involving the direct repressive action of SNAI1 on ER stress and Fgf21 expression, ultimately contributing to maintaining the proliferative and undifferentiated state of myoblasts.
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