FUNCTION AND REGULATION OF DE NOVO DNA METHYLTRANSFERASE DNMT3A1 IN MEMORY FORMATION

During learning and memory, transcription and epigenomic factors control the integration of new information in neurons through the regulation of expression of new proteins. However, the mechanisms that regulate learning-induced gene expression required for memory formation are not fully characterized. In this study, we investigate the mechanisms of regulation of DNA methyltransferase 3A1 (DNMT3A1) activity in response to neuronal activity and the contribution of DNMT3A1 to activity-induced gene expression and memory formation. Several studies demonstrate the requirement of de novo DNA methyltransferases, particularly DNMT3A, for memory formation. Dnmt3a encodes two isoforms: Dnmt3a1 and Dnmt3a2, both required for long-term memory formation. However, contrary to Dnmt3a2, the transcription of Dnmt3a1 is not regulated by neuronal activity. Interestingly, our preliminary mass spectrometry data indicates that DNMT3A1 is phosphorylated upon enhanced neuronal activity, leading to the hypothesis that DNMT3A1 is phosphorylated upon learning and that this modification is required for its role in memory formation. This is currently being investigated taking three distinct directions. First, we are identifying the kinases upstream of DNMT3A1 phosphorylation, second we are investigating the functional consequences of DNMT3A1 phosphorylation at the level of gene expression, chromatin binding and DNA methylation, and third its role in memory formation. This study has the potential to uncover a novel mechanism of the regulation of memory formation at both cellular and molecular levels.