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Vitamin C modulates TET1 function during somatic cell reprogramming

Nature Genetics volume 45, pages 1504–1509 (2013)Cite this article

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Abstract

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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Figure 1: Tet1 deficiency enhances iPSC generation in the presence of vitamin C.
Figure 2: Tet1 represses reprogramming in the presence of vitamin C.
Figure 3: Tet1 regulates genes related to MET and cell adhesion.
Figure 4: Tet1 represses reprogramming by blocking MET.

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Acknowledgements

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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  1. Jiekai Chen, Lin Guo and Lei Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. 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, China

    Jiekai Chen, Lin Guo, Haoyu Wu, Jiaqi Yang, He Liu, Xiaoshan Wang, Zhiwei Zhou, Jing Liu, Jiadong Liu, Hongling Wu, Kunlun Mo, Yingying Li, Keyu Lai, Jing Qi, Hongjie Yao, Guangjin Pan & Duanqing Pei

  2. Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,

    Jiekai Chen, Lin Guo, Jiaqi Yang, He Liu, Xiaoshan Wang, Zhiwei Zhou, Jing Liu, Hongling Wu, Kunlun Mo, Yingying Li, Keyu Lai, Jing Qi, Hongjie Yao, Guangjin Pan & Duanqing Pei

  3. Group of DNA Metabolism, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Lei Zhang, Xiao Hu, Tianpeng Gu, Shi-Qing Mao & Guo-Liang Xu

  4. Department of Biological Engineering, College of Pharmacy, Jilin University, Changchun, China

    Haoyu Wu

  5. School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China

    Jiadong Liu

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  1. Jiekai Chen
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Contributions

J.C., L.G. and L.Z. initiated the study, designed and performed experiments and analyzed data. Haoyu Wu performed the experiments and analyzed data. J.Y. and H.L. performed qPCR and chromatin immunoprecipitation experiments and prepared some cell samples. J.C. and X.W. performed bioinformatics analysis. X.H. performed reprogramming assays and chromatin immunoprecipitation. T.G. generated the antibody to TET1. Z.Z. bred the Tet1-null mice and derived primary cells. Jing Liu isolated primary cells and performed reprogramming assays. Jiadong Liu performed bisulfite genomic sequencing. Hongling Wu performed proliferation and apoptosis assays. S.-Q.M. generated the Tet1-null mice. K.M. performed blastocyst injections. Y.L. produced recombinant growth factor and assisted in antibody production. K.L. performed karyotype analysis. J.Q. performed protein blotting. H.Y. assisted in the construction of sequencing libraries. G.P. assisted in next-generation sequencing. G.-L.X. and D.P. conceived and supervised the entire study. D.P. and J.C. wrote the manuscript.

Corresponding authors

Correspondence to Guo-Liang Xu or Duanqing Pei.

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Chen, J., Guo, L., Zhang, L. et al. Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet 45, 1504–1509 (2013). https://doi.org/10.1038/ng.2807

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