Summary

Muscle stem cells, referred to as satellite cells, are essential for the regeneration of the skeletal muscle. These cells have been found to be regulated by an increasing number of transcriptional and epigenetic mechanisms. Chromatin remodelers, for instance, are epigenetic modulators that mobilize nucleosomes via an ATP-dependent mechanism. Here we show that the chromatin remodeler CHD4 (Mi-2β), a member of the Mi-2/nucleosome remodeling deacetylase (NuRD) repressive complex, is expressed in proliferating and differentiating satellite cells and is essential for their regenerative functions. Conditional deletion of the Chd4 gene in satellite cells impairs their proliferative expansion during muscle regeneration. Transcriptional analysis of Chd4-deficient satellite cells by RNA Sequencing (RNA-Seq) uncovered both the overexpression of the cell cycle inhibitors p21 (Cdkn1a), p57 (Cdkn1c) genes and the myogenic master regulatory transcription factors MyoD and Myogenin, together with the downregulation of cell-division and DNA damage response genes. Moreover, Chd4-deficient satellite cells upregulate genes corresponding to multiple tissues (e.g. skeletal muscle, heart and brain), suggesting an additional function for CHD4 in the repression of inappropriate genetic programs. Thus, CHD4 regulates satellite cell proliferation, DNA damage repair and fate commitment through an array of concerted actions. This study demonstrates for the first time a role for CHD4/NuRD complex in adult muscle regeneration by allowing successful satellite cell expansion. This contributes towards understanding the epigenetic regulation of satellite cells, which could pave the way to the potential discovery of innovative treatments for muscle diseases and conditions related to the impairment of muscle function such as aging.