Dnmt3a1 regulates memory formation via the downstram target Nrp1

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 for DNA methyltransferases (Dnmts) in memory formation whether individual Dnmts play unique or redundant functions in long-term memory formation is not well established. Furthermore, the downstream processes controlled by the Dnmts during the consolidation of memory are not investigated. In this study, we investigated the requirement for Dnmt3a1, the predominant Dnmt in the adult brain, in hippocampal long-term memory formation. Furthermore, we identified an activity-regulated Dnmt3a1-dependent genomic program. Our data showed that Dnmt3a1, similarly to its isoform Dnmt3a2, plays a critical role in memory formation. Furthermore, we uncovered Neuropilin 1 (Nrp1) as a downstream target of Dnmt3a1 during the formation of memory. Intriguingly, we found that Nrp1 expression is selectively regulated and a specific downstream effector of Dnmt3a1, but not Dnmt3a2. Taken together, our study uncovered a Dnmt3a isoform specific mechanism in memory formation and further highlighted the complex and highly regulated functions of distinct epigenetic regulators in brain function.