N6-methyladenine demethylase ALKBH1 inhibits the differentiation of skeletal muscle
N6-methyladenine demethylase ALKBH1 inhibits the differentiation of skeletal muscle
复制标题
N6-甲基腺嘌呤去甲基化酶ALKBH1抑制骨骼肌分化
DOI：
10.1016/j.yexcr.2021.112492
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发表时间：
2021-02-05
影响因子：
3.7
通讯作者：
Zhang, Qi
中科院分区：
文献类型：
--
作者：
Diao, Li-Ting;Xie, Shu-Juan;Zhang, Qi
DNA N-6-甲基腺嘌呤（N6-mA）是近年来发现的一种新的哺乳动物基因组表观遗传修饰，ALKBH 1是其脱甲基酶。敲除小鼠研究表明，ALKBH 1对于正常胚胎发育是不可或缺的。然而，ALKBH 1在肌发生中的功能在很大程度上是未知的。在这项研究中，我们发现，N6-mA表现出稳定的增加，沿着强烈下降的ALKBH 1在骨骼肌发育。ALKBH 1对C2 C12细胞的增殖有促进作用，对C2 C12细胞的分化有抑制作用。全基因组转录组分析和报告基因分析进一步揭示了ALKBH 1通过调节一组核心基因和多个信号通路实现分化抑制功能，包括增加趋化因子（C-X-C基序）配体14（CXCL 14）和激活ERK信号通路。综上所述，我们的结果表明，ALKBH 1是至关重要的C2 C12细胞的成肌分化，并建议N6-mA可能是一个新的表观遗传机制的调控肌发生。
DNA N-6-methyladenine (N6-mA) was recently recognized as a new epigenetic modification in mammalian genome, and ALKBH1 was discovered as its demethylase. Knock-out mice studies revealed that ALKBH1 was indispensable for normal embryonic development. However, the function of ALKBH1 in myogenesis is largely unknown. In this study, we found that N6-mA showed a steady increase, going along with a strong decrease of ALKBH1 during skeletal muscle development. Our results also showed that ALKBH1 enhanced proliferation and inhibited differentiation of C2C12 cells. Genome-wide transcriptome analysis and reporter assays further revealed that ALKBH1 accomplished the differentiation inhibiting function by regulating a core set of genes and multiple signaling pathways, including increasing chemokine (C-X-C motif) ligand 14 (CXCL14) and activating ERK signaling. Taken together, our results demonstrated that ALKBH1 is critical for the myogenic differentiation of C2C12 cells, and suggested that N6-mA might be a new epigenetic mechanism for the regulation of myogenesis.