Role of tet3 in the epigenetic regulation of neural stemness maintenance

Adult neural stem cells (NSCs) are able of unlimited self-renew while maintaining their capacity to differentiate. Since their discovery, NSCs have been extensively studied and the field is in continuous progress. The SVZ is the main active neurogenic niche in mice where sustained neurogenesis throughout life occurs. To explore the potential therapeutic use of these cells, the knowledge of their regulation is essential. There is evidence suggesting that epigenetic mechanisms like DNA methylation, histone modification and genomic imprinting can interact with transcriptional and environmental factors in NSCs modulating their plasticity and quiescence, as well as their differentiation capability, however these mechanisms are poorly understood in these cells. The generation of induced pluripotent stem cells (iPSCs) from somatic cells are a unique tool to study the particular properties of the cell of origin. Concretely, it is well described that important epigenetic barriers need to be overcome for a successful reprogramming into iPSCs. To have insights into the epigenetic mechanism regulating NSCs, we compare their epigenetic signature with the changes occurring on the epigenome during the acquisition of a pluripotent state, demonstrating that NSCs are in an intermediate state between differentiated cells and pluripotent cells. Importantly, in this process the epigenetic marks affecting imprinted genes are especially relevant. The recently described ten-eleven-translocation (TET) proteins, named as TET1, TET2 and TET3, are enzymes responsible for the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) that directly affects epigenetic regulation and, consequently, gene transcription. In this work, we show the especial role of TET3 in the reprogramming process as well as its role in neural stemness maintenance. We demonstrate that TET3 needs to be repressed for a successful reprogramming into iPSCs being the highest expressed member of the family in adult NSCs. Importantly, we also show that TET3 exerts its function on the stem cell pool of the SVZ, promoting their undifferentiated state and preventing the differentiation of neural stem cells into non-neurogenic astrocytes through the regulation of Snrpn, an imprinted gene located at the Prader-Willi syndrome gene cluster.