Abstract
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.
Highlights
The dentate gyrus of the hippocampus harbors a stem cell population that generates new neurons throughout life (Bond et al, 2015; Kempermann et al, 2015)
To first investigate whether DNA methylation patterns are dynamic during adult hippocampal neurogenesis in mice, we isolated neural precursor cells (NPCs) from the adult mouse hippocampus, differentiated them in vitro and isolated differentiated neurons by fluorescence-activated cell sorting (FACS; Fig 1A and Appendix Fig S1A and B)
To gain first insight into a potential role of the identified DNA methylation changes in controlling adult hippocampal neurogenesis, we annotated differentially methylated CpGs to the nearest located gene and performed gene set enrichment analysis with genes listed in the Mammalian Adult Neurogenesis Gene Ontology (MANGO; Overall et al, 2012)
Summary
The dentate gyrus of the hippocampus harbors a stem cell population that generates new neurons throughout life (Bond et al, 2015; Kempermann et al, 2015). Adult hippocampal neural stem and progenitor cells (NSPCs) originate from a specific population of embryonic NSPCs, which is highly proliferative during development but transitions to a quiescent state postnatally once the hippocampus is formed (Berg et al, 2019). A number of transcription factors controlling this process have been identified (Beckervordersandforth et al, 2015; Mukherjee et al, 2016; Sch€affner et al, 2018), the epigenetic machinery which enables the molecular changes required for the generation of functional neurons from NSPCs in the adult hippocampus has remained elusive
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