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

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 (), Shuibin Lin () and Quan Yuan ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06898-4

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