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Cell Stem Cell. 2014 Apr 3;14(4):512-22. doi: 10.1016/j.stem.2014.01.001. Epub 2014 Feb 13.

Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming.

Author information

1
Shanghai Key Laboratory of Molecular Andrology, The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
2
CAS Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
3
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine and BCMP, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
4
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
5
Shanghai Key Laboratory of Molecular Andrology, The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: glxu@sibs.ac.cn.

Abstract

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.

PMID:
24529596
DOI:
10.1016/j.stem.2014.01.001
[Indexed for MEDLINE]
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