De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis

Adult neurogenesis enables the life‐long addition of functional neurons to the hippocampus and is regulated by both cell‐intrinsic molecular programs and behavioral activity. De novo DNA methylation is crucial for embryonic brain development, but its role during adult hippocampal neurogenesis has remained unknown. Here, we show that de novo DNA methylation is critical for maturation and functional integration of adult‐born neurons in the mouse hippocampus. Bisulfite sequencing revealed that de novo DNA methyltransferases target neuronal enhancers and gene bodies during adult hippocampal neural stem cell differentiation, to establish neuronal methylomes and facilitate transcriptional up‐regulation of neuronal genes. Inducible deletion of both de novo DNA methyltransferases Dnmt3a and Dnmt3b in adult neural stem cells did not affect proliferation or fate specification, but specifically impaired dendritic outgrowth and synaptogenesis of newborn neurons, thereby hampering their functional maturation. Consequently, abolishing de novo DNA methylation modulated activation patterns in the hippocampal circuitry and caused specific deficits in hippocampus‐dependent learning and memory. Our results demonstrate that proper establishment of neuronal methylomes during adult neurogenesis is fundamental for hippocampal function. SYNOPSIS De novo DNA methyltransferases are required for the morphological and functional maturation of adult‐born neurons in the hippocampus. Adult neural stem cell proliferation and fate determination are unaffected by loss of de novo DNA methylation. Dnmt3a/b‐dependent enhancer methylation facilitates the upregulation of neuron‐specific genes during neuronal differentiation of adult hippocampal stem cells. De novo DNA methyltransferases Dnmt3a/b control maturation rate, dendritic outgrowth and spine formation of adult‐born neurons in the hippocampus. Conditional knock‐out of Dnmt3a/b during adult neurogenesis modifies experience‐dependent neuronal activation in the hippocampal circuitry. Expression of de novo DNA methyltransferases during adult neurogenesis is required for hippocampus‐dependent cognitive flexibility. Graphical Abstract Ablation of DNA methyltransferases Dnmt3a/b shows that de novo DNA methylation is not needed for adult neural stem cell proliferation and fate determination, but for morphological and functional maturation of adult‐born neurons in the hippocampus.