CHD7 Regulates Bone-fat Balance via Suppressing PPAR-? Signaling Pathway

Chromodomain helicase DNA-binding protein 7 (CHD7) is an ATP-dependent eukaryotic chromatin remodeling enzyme that plays a critical role in epigenetics. Previous studies showed CHD7 is essential in development of organs and mutation of CHD7 is the main cause of CHARGE syndrome, but the function of CHD7 in skeletal system remained elusive. Here we show that conditional knockout of Chd7 in bone marrow mesenchymal stem cells (MSCs) and pre-osteoblasts leads to a pathological phenotype in mice, manifested as skeletal system development disorder, low bone mass and severely high marrow adiposity. Mechanistically, we identify up-regulated peroxisome proliferators-activated receptors (PPAR) signaling pathway in Chd7-deficient MSCs. Knockout of Chd7 reduces the restriction of PPAR-?, then PPAR-? associates with tri-methylated histone H3 at lysine 4 (H3K4me3), activates the transcription of the downstream adipogenic genes, and disrupts the balance between osteogenic and adipogenic differentiation. Our work illustrates the pathological manifestations of Chd7 mutation in MSCs and reveals novel epigenetic mechanism in skeletal health and diseases. Overall design: 12 samples were analyzed.