Tet3-Mediated DNA Demethylation Contributes to the Direct Conversion of Fibroblast to Functional Neuron

Abstract

The direct conversion of somatic cells to neurons by bypassing the multipotent cell state may be a powerful approach for personalized medicine. In addition to neuronal transcription factors and multiple small molecules, we find that epigenetic modification also contributes to the direct conversion of fibroblasts to neurons. Here, we show that Tet3, a DNA dioxygenase, can rapidly and efficiently convert fibroblasts directly into functional neurons. The induced neurons (iNs) express pan and mature neuronal markers such as Tuj1, Synapsin, and neuronal nuclei (NeuN). Gene expression profiles demonstrate distinct neuron-specific gene clusters in iNs compared with primary neurons. Induced neurons display maturing firing patterns and form functional synapses. Additionally, we observe that the level of 5hmC in iNs gradually increases during the time course of transdifferentiation. These findings suggest that DNA demethylation may regulate direct lineage commitment, representing an avenue for investigating the process of transdifferentiation.