2. Academic Validation
  3. SNAI1 is upregulated during muscle regeneration and represses FGF21 and ATF3 expression by directly binding their promoters

SNAI1 is upregulated during muscle regeneration and represses FGF21 and ATF3 expression by directly binding their promoters

  • FASEB J. 2022 Jul;36(7):e22401. doi: 10.1096/fj.202200215R.
Ines Elia 1,  Giulia Realini 1,  Vittoria Di Mauro 2 3,  Sara Borghi 4 5,  Laura Bottoni 1,  Salvatore Tornambè 1,  Libero Vitiello 6,  Stephen J Weiss 7,  Mario Chiariello 8,  Annalaura Tamburrini 9 10,  Salvatore Oliviero 9 10,  Francesco Neri 9,  Maurizio Orlandini 1,  Federico Galvagni 1
Affiliations

Affiliations

  • 1 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
  • 2 IRCCS-Humanitas Research Hospital, Rozzano, Italy.
  • 3 Institute of Genetic and Biomedical Research (IRGB), Milan Unit, National Research Council, Via Fantoli 16/15, Milan, 20138, Italy.
  • 4 Department of Pathology, NYU Grossman School of Medicine, New York, New York, USA.
  • 5 Immune Monitoring Laboratory, NYU Langone Health, 550 First Avenue, New York, NY, 10016, USA.
  • 6 Department of Biology, University of Padova, Padova, Italy.
  • 7 Division of Genetic Medicine, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
  • 8 Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR) and Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Siena, Italy.
  • 9 Department of Life Science and Systems Biology, Università degli Studi di Torino, Turin, Italy.
  • 10 IIGM - Italian Institute for Genomic Medicine, c/o IRCCS, Candiolo, Italy.
PMID: 35726676 DOI: 10.1096/fj.202200215R
Abstract

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.

Keywords

E box; endoplasmic reticulum stress; gene silencing; microarray analysis; muscle regeneration; myoblast differentiation; promoter; skeletal muscle; transcription.

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