2. Academic Validation
  3. Setdb1 protects genome integrity in murine muscle stem cells to allow for regenerative myogenesis and inflammation

Setdb1 protects genome integrity in murine muscle stem cells to allow for regenerative myogenesis and inflammation

  • Dev Cell. 2024 Jun 5:S1534-5807(24)00329-0. doi: 10.1016/j.devcel.2024.05.012.
Pauline Garcia 1,  William Jarassier 1,  Caroline Brun 1,  Lorenzo Giordani 2,  Fany Agostini 1,  Wai Hing Kung 3,  Cécile Peccate 2,  Jade Ravent 1,  Sidy Fall 1,  Valentin Petit 4,  Tom H Cheung 3,  Slimane Ait-Si-Ali 4,  Fabien Le Grand 5
Affiliations

Affiliations

  • 1 Université Claude Bernard-Lyon 1, CNRS UMR 5261, Inserm U1315, Institut NeuroMyoGène, Pathophysiology and Genetics of Neuron and Muscle Unit, 69008 Lyon, France.
  • 2 Sorbonne Université, Inserm UMRS 974, Institut de Myologie, Myology Research Center Unit, 75013 Paris, France.
  • 3 Division of Life Science, Center for Stem Cell Research, HKUST-Nan Fung Life Sciences Joint Laboratory, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 4 Université Paris Cité, CNRS, Epigenetics and Cell Fate, UMR 7216, 75013 Paris, France.
  • 5 Université Claude Bernard-Lyon 1, CNRS UMR 5261, Inserm U1315, Institut NeuroMyoGène, Pathophysiology and Genetics of Neuron and Muscle Unit, 69008 Lyon, France. Electronic address: fabien.le-grand@cnrs.fr.
PMID: 38848717 DOI: 10.1016/j.devcel.2024.05.012
Abstract

The histone H3 lysine 9 methyltransferase SETDB1 controls transcriptional repression to direct stem cell fate. Here, we show that Setdb1 expression by adult muscle stem cells (MuSCs) is required for skeletal muscle regeneration. We find that SETDB1 represses the expression of endogenous retroviruses (ERVs) in MuSCs. ERV de-repression in Setdb1-null MuSCs prevents their amplification following exit from quiescence and promotes cell death. Multi-omics profiling shows that chromatin decompaction at ERV loci activates the DNA-sensing cGAS-STING pathway, entailing cytokine expression by Setdb1-null MuSCs. This is followed by aberrant infiltration of inflammatory cells, including pathological macrophages. The ensuing histiocytosis is accompanied by myofiber necrosis, which, in addition to progressive MuSCs depletion, completely abolishes tissue repair. In contrast, loss of Setdb1 in fibro-adipogenic progenitors (FAPs) does not impact immune cells. In conclusion, genome maintenance by SETDB1 in an adult somatic stem cell is necessary for both its regenerative potential and adequate reparative inflammation.

Keywords

SETDB1; cGAS-STING pathway; endogeneous retrovirus; inflammation; muscle regeneration; muscle stem cells; necrosis; transposable element.

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