Vitamin C, a micronutrient known for its anti-scurvy activity in humans, promotes the generation of induced pluripotent stem cells (iPSCs)1 through the activity of histone demethylating dioxygenases2,3. TET hydroxylases are also dioxygenases implicated in active DNA demethylation4,5,6,7,8. Here we report that TET1 either positively or negatively regulates somatic cell reprogramming depending on the absence or presence of vitamin C. TET1 deficiency enhances reprogramming, and its overexpression impairs reprogramming in the context of vitamin C2,9 by modulating the obligatory mesenchymal-to-epithelial transition (MET)10,11. In the absence of vitamin C, TET1 promotes somatic cell reprogramming independent of MET. Consistently, TET1 regulates 5-hydroxymethylcytosine (5hmC) formation at loci critical for MET in a vitamin C–dependent fashion. Our findings suggest that vitamin C has a vital role in determining the biological outcome of TET1 function at the cellular level. Given its benefit to human health, vitamin C should be investigated further for its role in epigenetic regulation.
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Gene Expression Omnibus
We are grateful to J. Nie, J. Zhu, B. Wei, X. Li, T. Peng, X. Huang and C. Tan for technical assistance. We thank H. Zheng for constructive criticism. We deeply appreciate the work of X. Zhao, H. Song, S. Chu and Y. Chen in blastocyst injection, and we thank R. Luo for isolating MEFs. We thank S. Gao (National Institute of Biological Sciences, China) for providing the FUW-TetOn-Tet1 vector. We wish to thank all members of our laboratories for their support. This work is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDA01020401), the National Basic Research Program of China (grants 2014CB965200, 2012CB966802 and 2011CB965204), Guangdong Natural Science Funds for Distinguished Young Scholars (grant S2013050014040), the National Natural Science Foundation of China (grants 31271357, 31230039, 31221001 and 91213304), the Ministry of Science and Technology International Technology Cooperation Program (grant 2012DFH30050), the Science and Technology Planning Project of Guangdong Province (grant 2011A060901019), the National Science & Technology Major Special Project on Major New Drug Innovation (grant 2011ZX09102-010), the Youth Innovation Promotion Association of the Chinese Academy of Sciences and the Guangzhou Pearl River Nova program (grant 2012J2200070).
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About this article
Free Radical Biology and Medicine (2019)