Neuronal DNA Methyltransferases: Epigenetic Mediators between Synaptic Activity and Gene Expression?

Abstract

DNMT3A and 3B are the main de novo DNA methyltransferases (DNMTs) in the brain that introduce new methylation marks to non-methylated DNA in postmitotic neurons. DNA methylation is a key epigenetic mark that is known to regulate important cellular processes in neuronal development and brain plasticity. Accumulating evidence disclosed rapid and dynamic changes in DNA methylation of plasticity-relevant genes that are important for learning and memory formation. To understand how DNMTs contribute to brain function and how they are regulated by neuronal activity is a prerequisite for a deeper appreciation of activity-dependent gene expression in health and disease. This review discusses the functional role of de novo methyltransferases and in particular DNMT3A1 in the adult brain with special emphasis on synaptic plasticity, memory formation, and brain disorders.

Keywords: DNA methylation; DNMT; cytosine methylation; learning; memory; neuroepigenetics; neuropsychiatric disorders.

Figure 1.

Dynamic and reversible cytosine methylation. (1) De novo DNA methyltransferase enzyme DNMT3 transfer methyl group to 5′-carbon in cytosine (C), converting it to 5mC. Maintenance DNA methyltransferase DNMT1 methylates the hemimethylated DNA. (2) TET enzymes initiative successive oxidation reactions steps, initially by converting 5mC to 5-hydroxy-methylcytosine (5hmC). (3) TET enzyme converts 5hmC to 5′-formyl-cytosine (5fC). (4) TET enzyme further converts 5fC to 5′-carboxyl-cytosine (5caC). TDG either directly excises the glycosidic bond in 5fC (4b) or 5caC (5) generating an abasic site. (6) Base Excision Repair (BER) pathway includes the removal of the abasic site and replacement of the nucleotide.

Figure 2.

Domain structure of mammalian DNMTs. The regulatory N-terminal part and conserved catalytic C-terminal part are represented. Importantly, the arrangement of different domains in DNMT1 is controlled by long linker regions, which form tight interactions with surface clefts of the domains. Both the linkers and the clefts are subject to many reported PTMs in DNMT1, including phosphorylation, acetylation, and ubiquitination. These PTMs might directly control the positioning of these domains in DNMT1. The ADD domain has been implicated in the allosteric control of DNMT3A, as it interacts with the catalytic domain of the methyltransferase and inhibits its activity, indicating that PHD-like domain-mediated interactions with other proteins could have direct regulatory impacts on the catalytic activity of the MTase. NLS = nuclear localization signal; CXXC = two cysteines separated by two other residues; BAH1/2 = tandem bromo-adjacent homology; PWWP = Pro-Trp-Trp-Pro; ADD = ATRX-DNMT3-DNMT3L.

Figure 3.

Phosphorylation sites in DNMT3A (see www.phosphosite.org). In the upper panel, the predicted phosphorylation sites with a score of >0.8 are displayed. Two sites, Serine 199 and Threonine 834, are predicted to be phosphorylated by Protein Kinase C (PKC), which is activated by a series of molecular cascades upon Ca⁺⁺ influx into neurons. In the lower panel, other phosphorylation sites are displayed that were identified in phospho-proteomics studies with the number of references, which reported this phosphosite.

Figure 4.

An overview of the various external stimuli that lead to alterations in DNA-methylation in the brain to regulate plasticity-relevant gene expression. These include constraint stress, associative fear conditioning, the day and night cycle, social interaction, as well as an enriched environment.

Figure 5.

A diagram showing the mRNA levels of Dnmt3a isoforms from various brain regions, from various types of stimuli compared to the control levels in each study that are indicated by a dashed line. The references to these studies are as follows: 1, Miller and Sweatt 2007; 2, Morris and Monteggia 2014; 3, Mitchnick and others 2015; 4, Day and others 2013; 5, Oliveira and others 2012; 6, LaPlant and others 2010; 7, Sharma and others 2008; 8, Elliott and others 2016.