CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou 510530, China.
Cell Rep. 2020 Sep 8;32(10):108120. doi: 10.1016/j.celrep.2020.108120.
N-methyladenosine (mA), the most abundant reversible modification on eukaryote messenger RNA, is recognized by a series of readers, including the YT521-B homology domain family (YTHDF) proteins, which are coupled to perform physiological functions. Here, we report that YTHDF2 and YTHDF3, but not YTHDF1, are required for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). Mechanistically, we found that YTHDF3 recruits the PAN2-PAN3 deadenylase complex and conduces to reprogramming by promoting mRNA clearance of somatic genes, including Tead2 and Tgfb1, which parallels the activity of the YTHDF2-CCR4-NOT deadenylase complex. Ythdf2/3 deficiency represses mesenchymal-to-epithelial transition (MET) and chromatin silencing at loci containing the TEAD motif, contributing to decreased reprogramming efficiency. Moreover, RNA interference of Tgfb1 or the Hippo signaling effectors Yap1, Taz, and Tead2 rescues Ythdf2/3-defective reprogramming. Overall, YTHDF2/3 couples RNA deadenylation and regulation with the clearance of somatic genes and provides insights into iPSC reprogramming at the posttranscriptional level.
N6-甲基腺苷（m6A）是真核生物信使 RNA 上最丰富的一种可逆修饰，可被一系列识别蛋白识别，包括 YT521-B 同源结构域家族（YTHDF）蛋白，它们通过偶联来发挥生理功能。在这里，我们报告 YTHDF2 和 YTHDF3，但不是 YTHDF1，对于体细胞重编程为诱导多能干细胞（iPSCs）是必需的。从机制上讲，我们发现 YTHDF3 招募 PAN2-PAN3 脱腺苷酶复合物，并通过促进体细胞基因（包括 Tead2 和 Tgfb1）的 mRNA 清除来促进重编程，这与 YTHDF2-CCR4-NOT 脱腺苷酶复合物的活性平行。Ythdf2/3 缺陷抑制间充质到上皮的过渡（MET）和包含 TEAD 基序的基因座的染色质沉默，导致重编程效率降低。此外，Tgfb1 的 RNA 干扰或 Hippo 信号效应物 Yap1、Taz 和 Tead2 挽救了 Ythdf2/3 缺陷型重编程。总的来说，YTHDF2/3 将 RNA 脱腺苷酸化和调控与体细胞基因的清除偶联起来，为 iPSC 重编程提供了在转录后水平的见解。
