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

Gonca Bayraktar,Guilherme M Gomes,Oliver Stork,Michael R Kreutz,Syed A Raza,Pingan Yuanxiang,Ferah Yildirim,Anna Karpova,Shoji Tajima,Isao Suetake,Alessandro D Confettura

doi:10.1038/s41386-020-0780-2

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.

Highlights

It is widely believed that rapid and reversible DNA methylation is essential for the stability of long-term memory but very little is known about how synaptic signals can induce changes in DNA methylation to elicit enduring alterations in plasticity-related gene expression [1,2,3,4,5,6]
Synaptic activity controls levels of DNMT3A1 in neuronal nuclei DNMT3A1 is the major de novo DNA methyltransferase expressed in the adult brain [15]
Synaptic plasticity inducing stimuli elicit DNMT3A1 degradation in a GluN2A-dependent manner We addressed whether induction of N-methyl-Daspartate receptors (NMDAR)-dependent long-term potentiation (LTP), a form of plasticity that is considered to be a cellular model of learning and memory, impacts nuclear DNMT3A1 protein levels

Summary

Introduction

It is widely believed that rapid and reversible DNA methylation is essential for the stability of long-term memory but very little is known about how synaptic signals can induce changes in DNA methylation to elicit enduring alterations in plasticity-related gene expression [1,2,3,4,5,6]. N-methyl-Daspartate receptors (NMDAR) signaling to the nucleus is instrumental for learning and memory formation and is altered in schizophrenia as well as other neuropsychiatric disorders [9, 10]. Compelling evidence exists for learning-induced de novo DNA methylation with several studies showing the importance of active DNA methylation as well as demethylation in the hippocampus during memory consolidation [1, 11,12,13]. One of the target genes is the brain-derived neurotrophic factor (BDNF), which undergoes promoter-specific DNA demethylation in the CA1 region of the hippocampus during memory consolidation [14]. The underlying signaling machinery in this process is not well understood It is fundamentally unclear how synaptic signals conveyed to the nucleus impact mechanisms of DNA methylation and demethylation of the Bdnf promoter. Impaired spatial learning and memory, as well as attenuated CA1 long-term potentiation (LTP), have been reported following a forebrain specific DNMT gene knockout in principal neurons [16, 17]

Methods

Results

Conclusion