Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus


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Authors
Confettura, Alessandro D. 
Gomes, Guilherme M.  ORCID logo  https://orcid.org/0000-0001-8566-4284
Raza, Syed A. 
Abstract

Abstract: DNA methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known about 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 NMDARs 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. This results in deficits in promoter methylation of activity-dependent genes, as well as synaptic plasticity and 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 plasticity-relevant signals from GluN2A-containing NMDARs control activity-dependent DNA-methylation involved in memory formation.

Description
Keywords
Article, /631/378, /631/378/2584/1695, /13/1, /13/51, /13/106, /13/109, /13/95, /9/30, /14/19, /14/35, /14/63, /14, /96, /64/60, /82/80, article
Journal Title
Neuropsychopharmacology
Conference Name
Journal ISSN
0893-133X
1740-634X
Volume Title
45
Publisher
Springer International Publishing