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Mettl3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis

Author

Listed:
  • Yunshu Wu

    (Sichuan University)

  • Liang Xie

    (Sichuan University)

  • Mengyuan Wang

    (Sichuan University)

  • Qiuchan Xiong

    (Sichuan University)

  • Yuchen Guo

    (Sichuan University)

  • Yu Liang

    (Sun Yat-sen University)

  • Jing Li

    (Sichuan University)

  • Rui Sheng

    (Sichuan University)

  • Peng Deng

    (Sichuan University)

  • Yuan Wang

    (Sichuan University)

  • Rixin Zheng

    (Sichuan University)

  • Yizhou Jiang

    (Shenzhen University)

  • Ling Ye

    (Sichuan University)

  • Qianming Chen

    (Sichuan University)

  • Xuedong Zhou

    (Sichuan University)

  • Shuibin Lin

    (Sun Yat-sen University)

  • Quan Yuan

    (Sichuan University)

Abstract

N6-methyladenosine (m6A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the m6A methyltransferase Mettl3 in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice. Mettl3 loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover, Mettl3 overexpression in MSCs protects the mice from estrogen deficiency-induced osteoporosis. Mechanistically, we identify PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis as an important downstream pathway for m6A regulation in MSCs. Knockout of Mettl3 reduces the translation efficiency of MSCs lineage allocator Pth1r, and disrupts the PTH-induced osteogenic and adipogenic responses in vivo. Our results demonstrate the pathological outcomes of m6A mis-regulation in MSCs and unveil novel epitranscriptomic mechanism in skeletal health and diseases.

Suggested Citation

  • Yunshu Wu & Liang Xie & Mengyuan Wang & Qiuchan Xiong & Yuchen Guo & Yu Liang & Jing Li & Rui Sheng & Peng Deng & Yuan Wang & Rixin Zheng & Yizhou Jiang & Ling Ye & Qianming Chen & Xuedong Zhou & Shui, 2018. "Mettl3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06898-4
    DOI: 10.1038/s41467-018-06898-4
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    Cited by:

    1. Caojie Liu & Qiuchan Xiong & Qiwen Li & Weimin Lin & Shuang Jiang & Danting Zhang & Yuan Wang & Xiaobo Duan & Ping Gong & Ning Kang, 2022. "CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Yang Zhao & Jingyuan Ning & Hongqi Teng & Yalan Deng & Marisela Sheldon & Lei Shi & Consuelo Martinez & Jie Zhang & Annie Tian & Yutong Sun & Shinichi Nakagawa & Fan Yao & Hai Wang & Li Ma, 2024. "Long noncoding RNA Malat1 protects against osteoporosis and bone metastasis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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