De novoDNA methylation controls neuronal maturation during adult hippocampal neurogenesis

Abstract

Dynamic DNA methylation controls gene-regulatory networks underlying cell fate specification. How DNA methylation patterns change during adult hippocampal neurogenesis and their relevance for adult neural stem cell differentiation and related brain function has, however, remained unknown. Here, we show that neurogenesis-associated de novo DNA methylation is critical for maturation and functional integration of adult-born hippocampal neurons. Cell stage-specific bisulfite sequencing revealed a pronounced gain of DNA methylation at neuronal enhancers, gene bodies and binding sites of pro-neuronal transcription factors during adult neurogenesis, which mostly correlated with transcriptional up-regulation of the associated loci. Inducible deletion of both de novo DNA methyltransferases Dnmt3a and Dnmt3b in adult neural stem cells specifically impaired dendritic outgrowth and synaptogenesis of new-born neurons, resulting in reduced hippocampal excitability and specific deficits in hippocampus-dependent learning and memory. Our results highlight that, during adult neurogenesis, remodeling of neuronal methylomes is fundamental for proper hippocampal function.

DNA methylation and hydroxymethylation characterize the identity of D1 and D2 striatal projection neurons

“…It is possible that 5mC is removed (or deposited) locally at some anchor points with the contribution of specific TFs 65 and that the modification spreads within a chromatin sub-domain. Alternatively, the transcriptional activity within the sub-domain during neuronal development could prevent DNA methyltransferase DNMT3A activity 66 which has been reported to play a role in depositing DNA 5mC de novo 67 and is essential for neuronal maturation 68 . The existence of 5mC differences spanning several genes and intergenic regions (e.g., Fig.…”

Role of primary aging hallmarks in Alzheimer´s disease

“…Although most of these CGI promoters remain transcriptionally active (high expression HCPs), others become silenced by recruited polycomb repressive complex 2 (PRC2), which catalyzes H3K27me3 [178][179][180], or become poised with the coexistence of H3K27me3 and an activating histone marker H3K4me3 (poised HCPs) [181,182]. Under stress conditions, the PRC2 catalytic subunit enhancer of zeste homolog 2 (EZH2) can recruit DNMTs, catalyzing de novo DNA methylation [183][184][185]. Critically, DNA methylation is enriched in poised promoters of AD susceptibility genes [168,169].…”