Institute of Environmental Medicine, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
EMBO Rep. 2020 Apr 3;21(4):e49229. doi: 10.15252/embr.201949229. Epub 2020 Feb 17.
N6-methyladenosine (m A) mRNA methylation has emerged as an important player in many biological processes by regulating gene expression. However, its roles in intestinal stem cell (ISC) homeostasis remain largely unknown. Here, we report that YTHDF1, an m A reader, is highly expressed in ISCs and its expression is upregulated by Wnt signaling at the translational level. Whereas YTHDF1 is dispensable for normal intestinal development in mice, genetic ablation of Ythdf1 dramatically blocks Wnt-driven regeneration and tumorigenesis with reduced ISC stemness. Mechanistically, YTHDF1 facilitates the translation of Wnt signaling effectors including TCF7L2/TCF4, while this process is enhanced during Wnt activation to augment β-catenin activity. Targeting YTHDF1 in ISCs of established tumors leads to tumor shrinkage and prolonged survival. Collectively, our studies unveil YTHDF1 as an amplifier of Wnt/β-catenin signaling at the translational level, which is required for the maintenance of ISCs during regeneration and tumorigenesis.
N6-甲基腺苷（m A）mRNA 甲基化通过调节基因表达，成为许多生物学过程中的重要调控因子。然而，其在肠道干细胞（ISC）稳态中的作用在很大程度上尚不清楚。在这里，我们报告说，m A 阅读器 YTHDF1 在 ISC 中高度表达，其表达在翻译水平上受到 Wnt 信号的上调。虽然 YTHDF1 对于正常的肠道发育在小鼠中是可有可无的，但 Ythdf1 的基因缺失会严重阻断 Wnt 驱动的再生和肿瘤发生，导致 ISC 干性降低。在机制上，YTHDF1 促进 Wnt 信号效应物（包括 TCF7L2/TCF4）的翻译，而这一过程在 Wnt 激活时会增强，以增加 β-连环蛋白的活性。在已建立的肿瘤中的 ISC 中靶向 YTHDF1 会导致肿瘤缩小和延长生存时间。总的来说，我们的研究揭示了 YTHDF1 作为 Wnt/β-连环蛋白信号在翻译水平上的放大器，它对于再生和肿瘤发生过程中 ISC 的维持是必需的。
