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

Xiao Hu; Lei Zhang; Shi Qing Mao; Zheng Li; Jiekai Chen; Run Rui Zhang; Hai Ping Wu; Juan Gao; Fan Guo; Wei Liu; Gui Fang Xu; Hai Qiang Dai; Yujiang Geno Shi; Xianlong Li; Boqiang Hu; Fuchou Tang; Duanqing Pei; Guoliang Xu

doi:10.1016/j.stem.2014.01.001

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

Xiao Hu
, Lei Zhang
, Shi Qing Mao
, Zheng Li
, Jiekai Chen
, Run Rui Zhang
, Hai Ping Wu
, Juan Gao
, Fan Guo
, Wei Liu
, Gui Fang Xu
, Hai Qiang Dai
, Yujiang Geno Shi
, Xianlong Li
, Boqiang Hu
, Fuchou Tang
, Duanqing Pei
, Guoliang Xu

Research output: Contribution to journal › Article › peer-review

284 Citations (Scopus)

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.

Original language	English
Pages (from-to)	512-522
Number of pages	11
Journal	Cell Stem Cell
Volume	14
Issue number	4
Early online date	13 Feb 2014
DOIs	https://doi.org/10.1016/j.stem.2014.01.001
Publication status	Published (in print/issue) - 3 Apr 2014

Funding

We thank Jiemin Wong, Pentao Liu, and Colum Walsh for critical reading of the manuscript. This work was supported by grants from the Ministry of Sciences and Technology of China (2012CB966903 and 2014CB964802), the National Science Foundation of China (31230039 and 31221001), the “Strategic Priority Research Program” of the Chinese Academy of Sciences (XDA01010301), and the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program” of China (grant number 2014ZX09507-002) to G.-L.X.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Hu, X., Zhang, L., Mao, S. Q., Li, Z., Chen, J., Zhang, R. R., Wu, H. P., Gao, J., Guo, F., Liu, W., Xu, G. F., Dai, H. Q., Shi, Y. G., Li, X., Hu, B., Tang, F., Pei, D., & Xu, G. (2014). Tet and TDG Mediate DNA Demethylation Essential for Mesenchymal-to-Epithelial Transition in Somatic Cell Reprogramming. Cell Stem Cell, 14(4), 512-522. https://doi.org/10.1016/j.stem.2014.01.001

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

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.",

author = "Xiao Hu and Lei Zhang and Mao, \{Shi Qing\} and Zheng Li and Jiekai Chen and Zhang, \{Run Rui\} and Wu, \{Hai Ping\} and Juan Gao and Fan Guo and Wei Liu and Xu, \{Gui Fang\} and Dai, \{Hai Qiang\} and Shi, \{Yujiang Geno\} and Xianlong Li and Boqiang Hu and Fuchou Tang and Duanqing Pei and Guoliang Xu",

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AU - Hu, Xiao

AU - Zhang, Lei

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AU - Li, Zheng

AU - Chen, Jiekai

AU - Zhang, Run Rui

AU - Wu, Hai Ping

AU - Gao, Juan

AU - Guo, Fan

AU - Liu, Wei

AU - Xu, Gui Fang

AU - Dai, Hai Qiang

AU - Shi, Yujiang Geno

AU - Li, Xianlong

AU - Hu, Boqiang

AU - Tang, Fuchou

AU - Pei, Duanqing

AU - Xu, Guoliang

PY - 2014/4/3

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N2 - 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.

AB - 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.

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

Abstract

Funding

UN SDGs

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