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

Caojie Liu, Qiuchan Xiong, Qiwen Li, Weimin Lin, Shuang Jiang, Danting Zhang, Yuan Wang, Xiaobo Duan, Ping Gong () and Ning Kang ()
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Caojie Liu: West China Hospital of Stomatology, Sichuan University
Qiuchan Xiong: West China Hospital of Stomatology, Sichuan University
Qiwen Li: West China Hospital of Stomatology, Sichuan University
Weimin Lin: West China Hospital of Stomatology, Sichuan University
Shuang Jiang: West China Hospital of Stomatology, Sichuan University
Danting Zhang: West China Hospital of Stomatology, Sichuan University
Yuan Wang: West China Hospital of Stomatology, Sichuan University
Xiaobo Duan: West China Hospital of Stomatology, Sichuan University
Ping Gong: West China Hospital of Stomatology, Sichuan University
Ning Kang: West China Hospital of Stomatology, Sichuan University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29633-6

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