Dataset Information

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

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.

SUBMITTER: Bayraktar G

PROVIDER: S-EPMC7547096 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Bayraktar Gonca G Yuanxiang PingAn P Confettura Alessandro D AD Gomes Guilherme M GM Raza Syed A SA Stork Oliver O Tajima Shoji S Suetake Isao I Karpova Anna A Yildirim Ferah F Kreutz Michael R MR

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20200729 12

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 neddylati ...[more]

PMID: 32726795

Similar Datasets

Project description:UnlabelledSynaptic vesicle (SV) pools must maintain a functional repertoire of proteins to efficiently release neurotransmitter. The accumulation of old or damaged proteins on SV membranes is linked to synaptic dysfunction and neurodegeneration. However, despite the importance of SV protein turnover for neuronal health, the molecular mechanisms underlying this process are largely unknown. Here, we have used dissociated rat hippocampal neurons to investigate the pathway for SV protein degradation. We find that neuronal activity drives the degradation of a subset of SV proteins and that the endosomal sorting complex required for transport (ESCRT) machinery and SV-associated GTPase Rab35 are key elements of this use-dependent degradative pathway. Specifically, neuronal activity induces Rab35 activation and binding to the ESCRT-0 protein Hrs, which we have identified as a novel Rab35 effector. These actions recruit the downstream ESCRT machinery to SV pools, thereby initiating SV protein degradation via the ESCRT pathway. Our findings show that the Rab35/ESCRT pathway facilitates the activity-dependent removal of specific proteins from SV pools, thereby maintaining presynaptic protein homeostasis.Significance statementSynaptic transmission is mediated by the release of chemical neurotransmitters from synaptic vesicles (SVs). This tightly regulated process requires a functional pool of SVs, necessitating cellular mechanisms for removing old or damaged proteins that could impair SV cycling. Here, we show that a subset of SV proteins is degraded in an activity-dependent manner and that key steps in this degradative pathway are the activation of the small GTPase Rab35 and the subsequent recruitment of the endosomal sorting complex required for transport (ESCRT) machinery to SV pools. Further, we demonstrate that ESCRT-0 component Hrs is an effector of Rab35, thus providing novel mechanistic insight into the coupling of neuronal activity with SV protein degradation and the maintenance of functional SV pools.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets