Tet and TDG Mediate DNA Demethylation Essential for Mesenchymal-to-Epithelial Transition in Somatic Cell Reprogramming
Tet and TDG Mediate DNA Demethylation Essential for Mesenchymal-to-Epithelial Transition in Somatic Cell Reprogramming
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Tet 和 TDG 介导 DNA 去甲基化对于体细胞重编程中间充质到上皮的转变至关重要
DOI：
10.1016/j.stem.2014.01.001
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发表时间：
2014-04-03
期刊：
影响因子：
23.9
通讯作者：
Xu, Guo-Liang
中科院分区：
文献类型：
--
作者：
Hu, Xiao;Zhang, Lei;Xu, Guo-Liang
泰特介导的DNA氧化是最近发现的哺乳动物表观遗传修饰，其在细胞命运转变中的功能作用仍然知之甚少。在这里，我们得到小鼠胚胎成纤维细胞（MEFs）删除所有三个泰特基因，并检查其重新编程为诱导多能干细胞（iPSC）的能力。我们发现，Tet-deficient MEFs不能重编程，因为在间充质上皮过渡（MET）的步骤中的块。TDG缺陷的MEFs的重编程也同样受损。重编程的阻断至少部分是由关键miRNA的缺陷激活引起的，这取决于泰特和TDG促进的氧化去甲基化。重新引入受影响的miRNA或催化活性的泰特和TDG恢复敲除MEF中的重编程。因此，促进基因活化的氧化去甲基化似乎是成纤维细胞重编程为多能性的功能所需的。这些发现为表观遗传障碍在细胞谱系转换中的作用提供了机制性的见解。
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 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.