Institute of Clinical Science, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
Department of Systems Biology, Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Mol Cell. 2018 Mar 15;69(6):1028-1038.e6. doi: 10.1016/j.molcel.2018.02.015.
N-methyladenosine (mA) is an abundant modification in eukaryotic mRNA, regulating mRNA dynamics by influencing mRNA stability, splicing, export, and translation. However, the precise mA regulating machinery still remains incompletely understood. Here we demonstrate that ZC3H13, a zinc-finger protein, plays an important role in modulating RNA mA methylation in the nucleus. We show that knockdown of Zc3h13 in mouse embryonic stem cell significantly decreases global mA level on mRNA. Upon Zc3h13 knockdown, a great majority of WTAP, Virilizer, and Hakai translocate to the cytoplasm, suggesting that Zc3h13 is required for nuclear localization of the Zc3h13-WTAP-Virilizer-Hakai complex, which is important for RNA mA methylation. Finally, Zc3h13 depletion, as does WTAP, Virilizer, or Hakai, impairs self-renewal and triggers mESC differentiation. Taken together, our findings demonstrate that Zc3h13 plays a critical role in anchoring WTAP, Virilizer, and Hakai in the nucleus to facilitate mA methylation and to regulate mESC self-renewal.
N6-甲基腺苷（m6A）是真核 mRNA 中的一种丰富修饰，通过影响 mRNA 稳定性、剪接、输出和翻译来调节 mRNA 动态。然而，精确的 m6A 调节机制仍不完全清楚。在这里，我们证明 ZC3H13，一种锌指蛋白，在核内调节 RNA m6A 甲基化中发挥重要作用。我们发现，在小鼠胚胎干细胞中敲低 Zc3h13 会显著降低 mRNA 上的全局 m6A 水平。在 Zc3h13 敲低后，大多数 WTAP、Virilizer 和 Hakai 易位到细胞质中，表明 Zc3h13 对于 Zc3h13-WTAP-Virilizer-Hakai 复合物的核定位是必需的，这对于 RNA m6A 甲基化很重要。最后，Zc3h13 耗竭，与 WTAP、Virilizer 或 Hakai 一样，会损害自我更新并触发 mESC 分化。总之，我们的研究结果表明，Zc3h13 在锚定 WTAP、Virilizer 和 Hakai 在核内以促进 m6A 甲基化和调节 mESC 自我更新方面发挥着关键作用。
