PPARγ forms a bridge between DNA methylation and histone acetylation at the C/EBPα gene promoter to regulate the balance between osteogenesis and adipogenesis of bone marrow stromal cells

Authors

  • Qing-hua Zhao,

    1. Department of Orthopaedics, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, China
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    • These authors contributed equally to this work
  • Shou-guo Wang,

    1. Department of Orthopaedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China
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    • These authors contributed equally to this work
  • Shao-xian Liu,

    1. Department of Orthopaedic Surgery, YanTaiShan Hospital, Yantai, ShanDong, China
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  • Ji-peng Li,

    1. Department of Orthopaedics, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, China
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  • Yong-xing Zhang,

    1. Department of Orthopaedics, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, China
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  • Zhong-yi Sun,

    1. Department of Orthopaedics, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, China
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  • Qi-ming Fan,

    Corresponding author
    1. Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, China
    • Correspondence

      Q. Fan, Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China

      Fax: +86 21 63137020

      Tel: +86 21 63137020

      E-mail: chillow@163.com

      J. Tian, Department of Orthopaedics, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China

      Fax: +86 21 63241377

      Tel: +86 21 37798566

      E-mail: gloria82@163.com

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  • Ji-wei Tian

    Corresponding author
    1. Department of Orthopaedics, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, China
    • Correspondence

      Q. Fan, Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China

      Fax: +86 21 63137020

      Tel: +86 21 63137020

      E-mail: chillow@163.com

      J. Tian, Department of Orthopaedics, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China

      Fax: +86 21 63241377

      Tel: +86 21 37798566

      E-mail: gloria82@163.com

    Search for more papers by this author

Abstract

The balance between osteogenesis and adipogenesis of bone marrow stromal cells is impaired in many human diseases. Knowledge of how to fine-tune this balance is of medical importance. CCAAT/enhancer binding protein α (C/EBPα) has been shown to regulate the balance between osteogenesis and adipogenesis of C3H10T1/2 cells, with epigenetic modifications of the C/EBPα promoter playing an important role. The present study aimed to elucidate the underlying molecular mechanisms. The results showed that peroxisome proliferator-activated receptor γ (PPARγ) binds the −1286 bp/−1065 bp region of the C/EBPα promoter to activate C/EBPα expression during osteogenesis and adipogenesis of C3H10T1/2 cells. DNA hypermethylation in the −1286 bp/−1065 bp region, observed at the terminal stage of osteogenesis, prevented PPARγ binding, and then histone deacetylase 1 (HDAC1) occupied this region to reduce the level of histone acetylation. We regulated the balance between osteogenesis and adipogenesis of mouse bone marrow stromal cells through modulation of DNA methylation and histone acetylation status. In addition, in bone marrow stromal cells from the glucocorticoid-induced osteoporosis (GIO) mouse, hypomethylation of CpG sites, higher binding of PPARγ, acetylated histones 3 and 4, and reduced binding of HDAC1 in the −1286 bp/−1065 bp region of C/EBPα promoter were observed, compared with normal mice. This study provides a deeper insight into the molecular mechanisms underlying the balance between osteogenesis and adipogenesis regulated by C/EBPα in synergy with PPARγ, and suggests a molecular model for how DNA methylation and histone acetylation are linked by PPARγ to regulate differentiation of bone marrow stromal cells.

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