Ten-Eleven Translocation 2 regulates adult neurogenesis through modulating 5mC oxidation dynamics at distinct regulatory elements. Mus musculus

Emerging evidence suggests that various epigenetic mechanisms play important roles in regulating adult neurogenesis. Ten-Eleven Translocation (Tet) proteins, the 5mC dioxygenases, could convert 5mC stepwise to 5-hydroxymethylcytosine (5hmC) and its further oxidation products, which constitute active DNA demethylation pathway. Here we show that unlike embryonic stem cells, 5hmC is acquired upon differentiation of adult neural stem cells (NSCs). The loss of Tet2 in proliferating NSCs significantly decreases their 5hmC abundance and partially blocks the acquisition of 5hmC upon differentiation, leading to the increased proliferation and reduced differentiation both in vitro and in vivo. This impaired neurogenesis process results in a defect of learning and memory as well as depressive behavior in Tet2-/- animals. Biochemical and epigenomic analyses reveal that transcription factor Forkhead box O3 (Foxo3a) physically interacts with Tet2 and orchestrates with various forms cytosine modifications to regulate different cohorts of gene expression through distinct mechanisms. These data together establish a novel and fundamental role of Tet2 in neurogenesis by coordinating with Foxo3a to epigenetically regulate the expression of key genes involved in neurogenesis. Overall design: Examine the roles of Tet2, Foxo3a and cytosine modifications in the neurogenesis process.