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

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.