m6A修饰是mRNA中最丰富的一种修饰类型，其形成受METTL3-METTL14复合物催化，由FTO和ALKBH5调控去甲基化，并能被YTH家族的蛋白所识别。m6A修饰参与mRNA的剪接、翻译、稳定性、降解和出核等RNA代谢过程，在细胞命运决定，生长发育和疾病发生中扮演重要角色。然而目前对m6A的阅读蛋白YTHDFs识别m6A修饰的mRNA后，如何影响mRNA的功能并参与细胞命运决定研究较少，特别是关于YTHDF3的功能仍有争议。本课题组发现敲降YTHDF2/3能够明显的抑制多能干细胞形成，且该功能依赖其识别m6A修饰的结构域。本项目拟基于这些前期工作，以体细胞重编程为细胞模型，深入研究YTHDFs在重编程中的功能，并进一步探索YTHDF2/3如何通过m6A修饰最终影响细胞命运决定的。该研究将系统地揭示m6A修饰的阅读蛋白YTHDFs在细胞命运决定过程中的功能和调控机制。

N6-methyladenosine (m6A) is the most abundant modification in mRNA, catalyzed by the METTL3-METTL14 complex, de-methylated by FTO and ALKBH5, and recognized by YTH family proteins. This modification regulates RNA metabolic processes, such as mRNA splicing, translation, stability, degradation, and nucleation as well as participates in cell fate determination, physiological development, and disease pathology. However, how m6A influences mRNA functions and impacts cell fate determination upon recognition via the m6A reading proteins, YTHDFs, is still unknown. In particular, the function of YTHDF3 is still controversial. Our preliminary data demonstrate that knockdown of YTHDF2/3 significantly inhibits the reprogramming of somatic cells into pluripotent stem cells. Moreover, the reprogramming efficiency depends on their m6A-binding domains. This project will utilize the somatic reprogramming model, aiming to further investigate the function of YTHDFs in reprogramming and m6A-dependent roles of YTHDF2/3 in cell fate decisions. Together, our study will systematically reveal the function and regulatory mechanism of YTHDFs in the process of cell fate determination.