YTHDF1-mediated translation amplifies Wnt-driven intestinal stemness
YTHDF1-mediated translation amplifies Wnt-driven intestinal stemness
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YTHDF1介导的翻译放大了Wnt驱动的肠干性
DOI：
10.15252/embr.201949229
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发表时间：
2020-02-17
期刊：
影响因子：
7.7
通讯作者：
Gao, Xiangwei
中科院分区：
文献类型：
--
作者：
Han, Bing;Yan, Sujun;Gao, Xiangwei
n6 -甲基腺苷（m(6)A） mRNA甲基化通过调节基因表达在许多生物过程中发挥着重要作用。然而，其在肠干细胞（ISC）稳态中的作用在很大程度上仍然未知。在这里，我们报道了YTHDF1，一个m(6)A阅读器，在ISCs中高表达，其表达在翻译水平上被Wnt信号上调。虽然YTHDF1对于小鼠的正常肠道发育是必不可少的，但基因消融YTHDF1会显著阻止wnt驱动的再生和肿瘤发生，从而降低ISC的干性。从机制上讲，YTHDF1促进了包括TCF7L2/TCF4在内的Wnt信号效应器的翻译，而这一过程在Wnt激活过程中得到增强，从而增强了β -连环蛋白的活性。在已建立肿瘤的ISCs中靶向YTHDF1可使肿瘤缩小并延长生存期。总的来说，我们的研究揭示了YTHDF1在翻译水平上作为Wnt/ β -catenin信号的放大器，这是在再生和肿瘤发生期间维持ISCs所必需的。
N6-methyladenosine (m(6)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(6)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 beta-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/beta-catenin signaling at the translational level, which is required for the maintenance of ISCs during regeneration and tumorigenesis.