Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis

• Published in: Nature communications 2017-06, Vol.8 (1), p.15903-15903, Article 15903
• Main Authors: Li, Xuekun, Yao, Bing, Chen, Li, Kang, Yunhee, Li, Yujing, Cheng, Ying, Li, Liping, Lin, Li, Wang, Zhiqin, Wang, Mengli, Pan, Feng, Dai, Qing, Zhang, Wei, Wu, Hao, Shu, Qiang, Qin, Zhaohui, He, Chuan, Xu, Mingjiang, Jin, Peng
• Format: Article
• Language: English
• Subjects: 13/100; 38/15; 38/39; 45; 5-Methylcytosine - analogs & derivatives; 5-Methylcytosine - metabolism; 631/208/176/1988; 631/532/2182; Animals; Cell Proliferation; Cells, Cultured; Demethylation; Deoxyribonucleic acid; Derivatives; Differentiation; DNA; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epigenetics; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; Forkhead protein; FOXO3 protein; Gene expression; Gene Expression Regulation; Genes; Genomes; Humanities and Social Sciences; In vitro methods and tests; Male; Mammals; Mice, Knockout; Molecular modelling; multidisciplinary; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurogenesis; Players; Protein Binding; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Science; Science (multidisciplinary); Stem cells; Translocation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15903

Emerging evidence suggests that active DNA demethylation machinery plays important epigenetic roles in mammalian adult neurogenesis; however, the precise molecular mechanisms and critical functional players of DNA demethylation in this process remain largely unexplored. Ten–eleven translocation (Tet) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and its downstream derivatives. Here we show that 5hmC is elevated during the differentiation of adult neural stem cells (aNSCs), and Tet2 is primarily responsible for modulating 5hmC dynamics. Depletion of Tet2 leads to increased aNSC proliferation and reduced differentiation in vitro and in vivo . Genome-wide transcriptional analyses reveal important epigenetic roles of Tet2 in maintaining the transcriptome landscape related to neurogenesis. Mechanistically, transcription factor forkhead box O3 (Foxo3a) physically interacts with Tet2 and regulates the expression of genes related to aNSC proliferation. These data together establish an important role for the Tet2-Foxo3a axis in epigenetically regulating critical genes in aNSCs during adult neurogenesis. Epigenetic modifications, such as DNA methylation, play an important role in adult neurogenesis. Here the authors show that Tet2, which converts 5mC to 5hmC, interacts with the transcription factor Foxo3a and regulates critical genes related to the proliferation and differentiation of adult neural stem cells.