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N6-adenomethylation of GsdmC is essential for Lgr5+ stem cell survival to maintain normal colonic epithelial morphogenesis
Developmental Cell ( IF 10.7 ) Pub Date : 2022-08-01 , DOI: 10.1016/j.devcel.2022.07.006
Jie Du 1 , Rajesh Sarkar 2 , Yan Li 3 , Lei He 2 , Wenjun Kang 3 , Wang Liao 4 , Weicheng Liu 2 , Tivoli Nguyen 2 , Linda Zhang 5 , Zifeng Deng 2 , Urszula Dougherty 2 , Sonia S Kupfer 2 , Mengjie Chen 6 , Joel Pekow 2 , Marc Bissonnette 2 , Chuan He 7 , Yan Chun Li 2
Affiliation  

Gut epithelial morphogenesis is maintained by intestinal stem cells. Here, we report that depletion of N6-adenosine methyltransferase subunit Mettl14 from gut epithelial cells in mice impaired colon mucosal morphogenesis, leading to increased mucosal permeability, severe inflammation, growth retardation, and premature death. Mettl14 ablation triggered apoptosis that depleted Lgr5+ stem cells and disrupted colonic organoid growth and differentiation, whereas the inhibition of apoptosis rescued Mettl14-deleted mice and organoids. Mettl14 depletion disrupted N6-adenomethylation on GsdmC transcripts and abolished GsdmC expression. Reconstitution of Mettl14-deleted organoids or mice with GSDMC rescued Lgr5 expression and prevented apoptosis and mouse premature death, whereas GSDMC silence eliminated LGR5 and triggered apoptosis in human colonic organoids and epithelial cells. Mechanistically, Mettl14 depletion eliminated mitochondrial GsdmC, disrupted mitochondrial membrane potential, and triggered cytochrome c release that activates the pro-apoptotic pathway. In conclusion, GsdmC N6-adenomethylation protects mitochondrial homeostasis and is essential for Lgr5+ cell survival to maintain normal colonic epithelial regeneration.



中文翻译:

GsdmC 的 N6 腺甲基化对于 Lgr5+ 干细胞存活以维持正常结肠上皮形态发生至关重要

肠上皮形态发生由肠干细胞维持。在此,我们报道小鼠肠道上皮细胞中N 6 -腺苷甲基转移酶亚基 Mettl14 的消耗会损害结肠粘膜形态发生,导致粘膜通透性增加、严重炎症、生长迟缓和过早死亡。Mettl14消融引发细胞凋亡,耗尽 Lgr5 +干细胞并破坏结肠类器官的生长和分化,而细胞凋亡的抑制则挽救了Mettl14缺失的小鼠和类器官。Mettl14 耗竭破坏了GsdmC转录本上的N 6 -腺甲基化并消除了 GsdmC 表达。用 GSDMC重建Mettl14缺失的类器官或小鼠可挽救 Lgr5 表达并防止细胞凋亡和小鼠过早死亡,而 GSDMC 沉默消除了 LGR5 并引发人结肠类器官和上皮细胞的细胞凋亡。从机制上讲,Mettl14 缺失消除了线粒体 GsdmC,破坏了线粒体膜电位,并触发细胞色素c释放,从而激活促凋亡途径。总之,GsdmC N 6 -腺甲基化可保护线粒体稳态,并且对于Lgr5 +细胞存活以维持正常结肠上皮再生至关重要。

更新日期:2022-08-01
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