Dnmt3a1 regulates hippocampus-dependent memory via the downstream target Nrp1

Abstract 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, 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 examined the requirement of the predominant Dnmt in the adult brain, Dnmt3a1, for hippocampus- dependent long-term memory formation. Using RNA-sequencing, we identified an activity- regulated Dnmt3a1-dependent genomic program in which several genes were functionally associated with functional and structural plasticity. Our data showed that Dnmt3a1, similarly to its isoform Dnmt3a2, plays a critical role in memory formation and identified Neuropilin 1 (Nrp1) as a downstream target of Dnmt3a1 in this process. Intriguingly, we found that Nrp1 expression is selectively regulated by and a specific downstream effector of Dnmt3a1, but not Dnmt3a2. 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.