Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis.
Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis.
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Mettl3介导的m6A RNA甲基化调节骨髓间充质干细胞和骨质疏松的命运
DOI：
10.1038/s41467-018-06898-4
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发表时间：
2018-11-14
影响因子：
16.6
通讯作者：
Yuan Q
中科院分区：
文献类型：
--
作者：
Wu Y;Xie L;Wang M;Xiong Q;Guo Y;Liang Y;Li J;Sheng R;Deng P;Wang Y;Zheng R;Jiang Y;Ye L;Chen Q;Zhou X;Lin S;Yuan Q
N6-甲基腺苷（m6 A）是真核生物中最丰富的表观遗传修饰，在哺乳动物发育和疾病控制过程中对多种RNA加工事件至关重要。在此，我们发现条件性敲除骨髓间充质干细胞（MSCs）中的m6 A甲基转移酶Mettl 3可诱导小鼠骨质疏松症的病理特征，Mettl 3功能丧失导致骨形成受损，成骨分化潜能不足和骨髓肥胖增加。此外，Mettl 3在MSC中的过表达保护小鼠免受雌激素缺乏诱导的骨质疏松症。从机制上讲，我们确定PTH（甲状旁腺激素）/Pth 1 r（甲状旁腺激素受体-1）信号轴作为MSC中m6 A调控的重要下游途径。Mettl 3的敲除降低了MSC谱系分配器Pthlr的翻译效率，并破坏了PTH诱导的体内成骨和成脂反应。我们的研究结果证明了MSC中m6 A错误调节的病理结果，并揭示了骨骼健康和疾病中新的表观转录机制。
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 methyltransferaseMettl3in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice.Mettl3loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover,Mettl3overexpression 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 ofMettl3reduces 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.
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