CHD7 Regulates Bone-fat Balance via Suppressing PPAR-γ 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-γ, then PPAR-γ 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. 12 samples were analyzed.

染色质域解旋酶DNA结合蛋白7（CHD7）是一种ATP依赖的真核染色质重塑酶，在表观遗传学中发挥关键作用。既往研究表明，CHD7对器官发育至关重要，而CHD7突变是CHARGE综合征的主要致病原因，但CHD7在骨骼系统中的功能仍未明确。本研究发现，在骨髓间充质干细胞（bone marrow mesenchymal stem cells, MSCs）和前成骨细胞中条件性敲除Chd7，会导致小鼠出现病理表型，具体表现为骨骼系统发育紊乱、骨量降低以及严重的骨髓脂肪堆积。从机制层面来看，本研究证实Chd7缺陷的MSCs中，过氧化物酶体增殖物激活受体（peroxisome proliferators-activated receptors, PPAR）信号通路表达上调。Chd7敲除会减弱对PPAR-γ的抑制作用，随后PPAR-γ与赖氨酸4位三甲基化组蛋白H3（H3K4me3）结合，激活下游成脂基因的转录，并破坏成骨与成脂分化之间的动态平衡。本研究阐明了Chd7突变在MSCs中的病理表现，并揭示了骨骼健康与疾病领域中一种全新的表观遗传调控机制。本研究共分析了12份样本。