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.

中文翻译：

---

从头 DNA 甲基化控制成年海马神经发生过程中的神经元成熟

成人神经发生使功能性神经元终生添加到海马体中，并受细胞内在分子程序和行为活动的调节。从头DNA 甲基化对胚胎大脑发育至关重要，但其在成年海马神经发生过程中的作用仍然未知。在这里，我们表明从头DNA 甲基化对于小鼠海马体中成年出生的神经元的成熟和功能整合至关重要。亚硫酸氢盐测序显示，从头DNA 甲基转移酶在成年海马神经干细胞分化过程中靶向神经元增强子和基因体，以建立神经元甲基化组并促进神经元基因的转录上调。两者的诱导性缺失成体神经干细胞中的从头DNA 甲基转移酶 Dnmt3a 和 Dnmt3b 不影响增殖或命运特化，但会特别损害新生神经元的树突生长和突触发生，从而阻碍它们的功能成熟。因此，消除从头DNA 甲基化调节海马回路中的激活模式，并导致海马依赖性学习和记忆的特定缺陷。我们的结果表明，在成人神经发生过程中正确建立神经元甲基化组是海马功能的基础。