Ding Chenbo, Yang Xinhui, Liu Hua, Roulis Manolis, Chen Huifang, Chen Yunzhu, Xu Hao, Gao Yimeng, Zhong Jie, Li Hua-Bing, Ye Youqiong, Cai Wei, Hu Weiguo, Wang Zhengting
Institute of Immunological Innovation & Translation, Chongqing Medical University, Chongqing 400016, China.
Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
J Mol Cell Biol. 2025 Jul 28;17(2). doi: 10.1093/jmcb/mjae060.
The development and homeostasis of intestinal epithelium are mediated by actively proliferating Lgr5+ stem cells, which possess a remarkable self-renewal and differentiation capacity. Recently, our study demonstrated that N6-methyladenosine (m6A) methylation was essential for the survival of colonic stem cells. Here, we show that methyltransferase-like 3 (METTL3) expression is downregulated in the colon mucosa in ulcerative colitis (UC) patients and strongly associated with the differentiation and maturation of goblet cells during inflammation. In mice, depletion of Mettl3 significantly inhibits the self-renewal and differentiation of Lgr5+ stem cells, especially the differentiation and maturation of goblet cells, resulting in intestinal dysplasia and spontaneous inflammation. Mechanistically, Mettl3 deletion-mediated m6A loss facilitates the expression levels of growth factor receptor binding protein 10 (Grb10) and interferon-related developmental regulator 1 (Ifrd1) via increasing their messenger RNA stability. We further demonstrate that the levels of GRB10 and IFRD1 are negatively correlated with METTL3 level in UC samples. Collectively, our data indicate that METTL3 enhances the self-renewal and differentiation of Lgr5+ stem cells during intestinal development and inflammation, and thus it may be a potential therapeutic target for UC treatment.
肠道上皮的发育和稳态由活跃增殖的Lgr5 +干细胞介导，这些干细胞具有显著的自我更新和分化能力。最近，我们的研究表明，N6-甲基腺苷（m6A）甲基化对结肠干细胞的存活至关重要。在这里，我们表明，甲基转移酶样3（METTL3）在溃疡性结肠炎（UC）患者的结肠黏膜中表达下调，并且在炎症期间与杯状细胞的分化和成熟密切相关。在小鼠中，Mettl3的缺失显著抑制Lgr5 +干细胞的自我更新和分化，尤其是杯状细胞的分化和成熟，导致肠道发育异常和自发性炎症。机制上，Mettl3缺失介导的m6A缺失通过增加生长因子受体结合蛋白10（Grb10）和干扰素相关发育调节因子1（Ifrd1）的信使RNA稳定性来促进它们的表达水平。我们进一步证明，在UC样本中，GRB10和IFRD1的水平与METTL3水平呈负相关。总的来说，我们的数据表明，METTL3在肠道发育和炎症过程中增强Lgr5 +干细胞的自我更新和分化，因此它可能是UC治疗的潜在治疗靶点。
