Dnmt3a1 regulates memory formation via the downstram target Nrp1
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ABSTRACT:
PROVIDER: PRJNA973052 | ENA |
REPOSITORIES: ENA
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Project description: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.
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Project description: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.
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