| Popis: |
DNA-methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3a1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDAR drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3a1 and results in deficits of promoter methylation of activity-dependent genes, synaptic plasticity as well as memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively the data show that GluN2A containing NMDAR control synapse-to-nucleus signaling that links plasticity-relevant signals to activity-dependent DNA-methylation involved in memory formation. |
