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Role of Chromatin Remodeling Genes and TETs in the Development of Human Midbrain Dopaminergic Neurons

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Abstract

Understanding epigenetic regulation in the differentiation and maturation of dopaminergic neurons is critical to improve and develop new medications for Parkinson’s disease (PD). To explore the role of ten-eleven translocation (TETs) family of dioxygenases and chromatin remodeling genes in the development of human midbrain dopaminergic (mDA) neurons, we globally analyze the epigenetic regulation of gene expression in human induced pluripotent stem cells (iPSCs) and iPSCs-derived mDA neurons. During the conversion of iPSCs into neuronal lineages of dopaminergic progenitors and mDA neurons, the expression patterns of epigenetic genes in multiple sets alter significantly. Vitamin C, an activator of TET enzymes, increases hydroxymethylcytosine (5hmC) level along with a higher yield of mDA neurons. Additionally, vitamin C treatment elevates gene expressions of TET2/3 and vitamin C transporters. Importantly, functional arrays indicate that vitamin C can promote neuronal maturation, synaptic activity, and dopamine release. Collectively, our study demonstrates that chromatin remodeling genes and the TET-5hmC pathway, which is regulated by vitamin C, are critical for the vital developmental stages of human mDA neurons.

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Acknowledgments

We are particularly grateful for the following grant support: National Natural Science Foundation of China (Grant no. 81572495, 81773264 and 81573239).

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Authors and Affiliations

  1. Center for Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, No.9, Tujialing, Wuchang District, Wuhan, 430064, Hubei, China

    Li Xiang, Wenjing Shu & Gaofeng Jiang

  2. Ministry of Education (MOE) Key Laboratory of Gene Function and Regulation, School of Life Sciences, State Key Laboratory of Biocontrol, Sun Yat-sen University, Guangzhou, 510006, Guangdong, China

    Guobin Huang

  3. Levi Regenerative Medicine Technologies, Zhuhai, 519085, Guangdong, China

    Guobin Huang, Chunli Gong & Hao Lu

  4. Center for Stem Cell Biology and Tissue Engineering, The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China

    Nan Cao

  5. Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China

    Rui Chen

  6. State Key Laboratory of Genetic Engineering, School of Life Sciences and Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, 200438, China

    Jixi Li

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  1. Li Xiang
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Contributions

L. X., G. H. and G. J. designed, performed most of the experiments, and wrote the manuscript. L. X. and G. H. performed mDA neuronal differentiation, qPCR, immunofluorescence, and biochemistry assays. W. S. and C. G. performed MEA analyses, dot blotting, and bioinformatics data processing. N. C., R. C., X. J., and H. L. provided reagents and critical comments. G. J. supervised the project and wrote the manuscript. All authors edited the manuscript.

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Correspondence to Gaofeng Jiang.

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Li Xiang and Guobin Huang are Co-first authors

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Xiang, L., Huang, G., Shu, W. et al. Role of Chromatin Remodeling Genes and TETs in the Development of Human Midbrain Dopaminergic Neurons. Stem Cell Rev and Rep 16, 718–729 (2020). https://doi.org/10.1007/s12015-020-09972-x

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