Tet and TDG Mediate DNA Demethylation Essential for Mesenchymal-to-Epithelial Transition in Somatic Cell Reprogramming

详细信息    查看全文

• 作者：Xiao Hu¹ ; ⁵ ; Lei Zhang¹ ; ⁵ ; Shi-Qing Mao¹ ; ⁵ ; Zheng Li¹ ; Jiekai Chen² ; Run-Rui Zhang¹ ; Hai-Ping Wu¹ ; Juan Gao¹ ; Fan Guo¹ ; Wei Liu¹ ; Gui-Fang Xu¹ ; Hai-Qiang Dai¹ ; Yujiang Geno Shi³ ; Xianlong Li⁴ ; Boqiang Hu⁴ ; Fuchou Tang⁴ ; Duanqing Pei² ; Guo-Liang Xu¹ ; ^{glxu@sibs.ac.cn" class="auth_mail}
• 刊名：Cell Stem Cell
• 出版年：3 April, 2014
• 年：2014
• 卷：14
• 期：4
• 页码：512-522
• 全文大小：4160 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Summary

Tet-mediated DNA oxidation is a recently identified mammalian epigenetic modification, and its functional role in cell-fate transitions remains poorly understood. Here, we derive mouse embryonic fibroblasts (MEFs) deleted in all three Tet genes and examine their capacity for reprogramming into induced pluripotent stem cells (iPSCs). We show that Tet-deficient MEFs cannot be reprogrammed because of a block in the mesenchymal-to-epithelial transition (MET) step. Reprogramming of MEFs deficient in TDG is similarly impaired. The block in reprogramming is caused at least in part by defective聽activation of key miRNAs, which depends on oxidative demethylation promoted by Tet and TDG. Reintroduction of either the affected miRNAs or catalytically active Tet and TDG restores reprogramming in the knockout MEFs. Thus, oxidative demethylation to promote gene activation appears to be functionally required for reprogramming of fibroblasts to pluripotency. These findings provide mechanistic insight into the role of epigenetic barriers in cell-lineage conversion.