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

Abstract

Modulations in chromatin structure orchestrate gene expression and direct stem cell fate. More specifically, the Histone 3 Lysine 9 Methyltransferase SETDB1 controls transcriptional repression to regulate pluripotency and self-renewal. While SETDB1 functions have been extensively studied in embryonic stem cells and in cancer cells, less is known on the role of SETDB1 in adult stem cells in vivo. Here, we show that SETDB1 expression by adult muscle stem cells (MuSCs) is absolutely required for muscle tissue regeneration following acute injury. We find that SETDB1 represses the expression of the endogenous retroviruses (ERVs) family of transposable elements in MuSCs. ERV re-expression in Setdb1-null MuSCs prevents their amplification following exit from quiescence and promotes cell death. Multi-omics profiling further shows that the absence of SETDB1 in MuSCs leads to the activation of the DNA-sensing cGAS-STING pathway, entailing activation of the Interferon pathway and increased cytokine expression. In vivo, the cytokine storm triggered by MuSCs devoid of Setdb1 provokes aberrant infiltration of inflammatory cells including the appearance of a pathological macrophage lineage. The ensuing histiocytosis results in necrosis of the newly formed muscle fibers and completely abolishes skeletal muscle tissue repair. In contrast, disruption of Setdb1 gene in another muscle-resident cell type, the fibro-adipogenic progenitors (FAPs), does not lead to any phenotype. In conclusion, the control of genome stability by SETDB1 in an adult somatic stem cell is necessary for both its regenerative potential and its adequate communication with the inflammatory cells regulating tissue repair.