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Chromodomain helicase DNA-binding protein 7 (CHD7), an ATP-dependent eukaryotic chromatin remodeling enzyme, is essential for the development of organs. The mutation of  CHD7  is the main cause of CHARGE syndrome, but its function and mechanism in skeletal system remain unclear. Here, we show conditional knockout of  Chd7  in bone marrow mesenchymal stem cells (MSCs) and preosteoblasts leads to a pathological phenotype manifested as low bone mass and severely high marrow adiposity. Mechanistically, we identify enhancement of the peroxisome proliferator-activated receptor (PPAR) signaling in  Chd7 -deficient MSCs. Loss of  Chd7  reduces the restriction of PPAR-γ and then PPAR-γ associates with trimethylated histone H3 at lysine 4 (H3K4me3), which subsequently activates the transcription of downstream adipogenic genes and disrupts the balance between osteogenic and adipogenic differentiation. Our data illustrate the pathological manifestations of  Chd7  mutation in MSCs and reveal an epigenetic mechanism in skeletal health and diseases.

CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling