Epigenetic factors are well-established players in memory formation. Specifically, DNA methylation is necessary for the formation of long-term memory in multiple brain regions including the hippocampus. Despite the demonstrated role of DNA methyltransferases (Dnmts) in memory formation, it is unclear whether individual Dnmts have unique or redundant functions in long-term memory formation. Furthermore, the downstream processes controlled by Dnmts during memory consolidation have not been investigated. In this study, we demonstrated that Dnmt3a1, the predominant Dnmt in the adult brain, is required for long-term spatial object recognition and contextual fear memory. Using RNA sequencing, we identified an activity-regulated Dnmt3a1-dependent genomic program in which several genes were associated with functional and structural plasticity. Furthermore, we found that some of the identified genes are selectively dependent on Dnmt3a1, but not its isoform Dnmt3a2. Specifically, we identified Neuropilin 1 (Nrp1) as a downstream target of Dnmt3a1 and further demonstrated the involvement of Nrp1 in hippocampus-dependent memory formation. Importantly, we found that Dnmt3a1 regulates hippocampus-dependent memory via Nrp1. In contrast, Nrp1 overexpression did not rescue memory impairments triggered by reduced Dnmt3a2 levels. Taken together, our study uncovered a Dnmt3a-isoform-specific mechanism in memory formation, identified a novel regulator of memory, and further highlighted the complex and highly regulated functions of distinct epigenetic regulators in brain function.

表观遗传因素在记忆形成中发挥着重要作用。具体来说，DNA甲基化对于包括海马体在内的多个大脑区域的长期记忆的形成是必要的。尽管 DNA 甲基转移酶 (Dnmts) 在记忆形成中的作用已被证明，但尚不清楚单个 Dnmts 在长期记忆形成中是否具有独特或冗余的功能。此外，内存整合过程中由 Dnmts 控制的下游过程尚未被研究。在这项研究中，我们证明了成人大脑中主要的 Dnmt Dnmt3a1 是长期空间物体识别和情境恐惧记忆所必需的。通过 RNA 测序，我们确定了一个活性调节的 Dnmt3a1 依赖性基因组程序，其中多个基因与功能和结构可塑性相关。此外，我们发现一些已识别的基因选择性依赖于 Dnmt3a1，但不依赖于其同工型 Dnmt3a2。具体来说，我们确定 Neuropilin 1 (Nrp1) 是 Dnmt3a1 的下游靶标，并进一步证明 Nrp1 参与海马依赖性记忆形成。重要的是，我们发现 Dnmt3a1 通过 Nrp1 调节海马依赖性记忆。相比之下，Nrp1 过度表达并不能挽救 Dnmt3a2 水平降低引发的记忆障碍。总而言之，我们的研究揭示了记忆形成中的 Dnmt3a 同工型特异性机制，确定了一种新型记忆调节因子，并进一步强调了不同表观遗传调节因子在大脑功能中的复杂且高度调节的功能。