The Role of Activity-Dependent DNA Demethylation in the Adult Brain and in Neurological Disorders

Abstract

Over the last decade, an increasing number of reports underscored the importance of epigenetic regulations in brain plasticity. Epigenetic elements such as readers, writers and erasers recognize, establish, and remove the epigenetic tags in nucleosomes, respectively. One such regulation concerns DNA-methylation and demethylation, which are highly dynamic and activity-dependent processes even in the adult neurons. It is nowadays widely believed that external stimuli control the methylation marks on the DNA and that such processes serve transcriptional regulation in neurons. In this mini-review, we cover the current knowledge on the regulatory mechanisms controlling in particular DNA demethylation as well as the possible functional consequences in health and disease.

Keywords: DNA Methylation; GADD45B; TET enzymes; base excision repair (BER); gene expression; neural disorders; neurons; synaptic plasticity.

Figure 1

Pathways of active DNA demethylation. Since the formerly hypothesized demethylase to directly convert 5-methylcytosine (5mC) to cytosine (Cyt) has not been identified, we depict here the current view how active DNA demethylation might take place. 5mC is oxidized by ten-eleven translocation (TET) family of dioxygenases to generate 5-hydroxymethylcytosine (5hmC). In successive steps TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine DNA glycosylase (TDG) recognizes intermediate DNA forms 5fC and 5caC and excises the glycosidic bond resulting in an apyrimidinic (AP) site. In an alternative deamination pathway 5hmC can be deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to Thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Nei-Like DNA Glycosylase 1 (NEIL1), or methyl-CpG binding protein 4 (MBD4). AP sites and T:G mismatches can be efficiently repaired by Base Excision Repair (BER) enzymes. Dotted lines indicate a proposed but not experimentally proven path.

Figure 2

Schematic presentation of the known domain structures of proteins involved in DNA methylation/demethylation. DNMT3A1/2: ADD domain of DNMT3A1/2 is involved in the allosteric control of the enzyme. TET enzymes: DNA binding CXXC motif is present in TET1 and TET3. Double-stranded β-helix (DSβH) is the fold core oxygenase domain is preceded by a cysteine (Cys)-rich domain. Sumo-binding motifs (SBM) and catalytic residues (in blue) of TDG is represented. PWWP: Pro-Trp-Trp-Pro; CXXC: Cys-X-X-Cys motif.