Diverse and dynamic DNA modifications in brain and diseases

Abstract

DNA methylation is a class of epigenetic modification essential for coordinating gene expression timing and magnitude throughout normal brain development and for proper brain function following development. Aberrant methylation changes are associated with changes in chromatin architecture, transcriptional alterations and a host of neurological disorders and diseases. This review highlights recent advances in our understanding of the methylome's functionality and covers potential new roles for DNA methylation, their readers, writers, and erasers. Additionally, we examine novel insights into the relationship between the methylome, DNA-protein interactions, and their contribution to neurodegenerative diseases. Lastly, we outline the gaps in our knowledge that will likely be filled through the widespread use of newer technologies that provide greater resolution into how individual cell types are affected by disease and the contribution of each individual modification site to disease pathogenicity.

Figure 1

Generation of DNA modifications. (A) Mechanisms of cytosine methylation and demethylation. Cytosine (C) is converted to 5mC by DNMT enzymes. TET enzymes further catalyze the oxidization of 5mC to 5hmC, 5fC and 5CaC. (B) Potential mechanisms of DNA 6mA methylation and demethylation. 6mA is potentially catalyzed by DNA N6-methyl methyltransferase (DAMT1) in worm. N(6) adenine-specific DNA methyltransferase 1 (N6AMT1) and methyltransferase-like protein 4 (METTL4) have been found to catalyze 6mA deposition in mammals. DNA N6-methyl adenine demethylase (NMAD1) has been shown to have 6mA demethylation activity in worm, and 6mA demethylase (DMAD) was identified as a 6mA demethylase in fly. Alpha-ketogluterate-dependent dioxygenase AlkB homolog 1 (ALKBH1) and 4 (ALKBH4) were found to mediate 6mA removal in mammals.

Figure 2

DNA modifications associated with active and repressed transcriptional states. Generally, the enhancer regions of actively transcribed genes contain unmethylated cytosine and hydroxymethylated cytosine residues spanning the enhancer region. The regions flanking the TSS contain both methylated and hydroxymethylated cytosines. In the immediate vicinity of the TSS, the CpG sites are unmethylated. 5hmC and 5mC are dispersed throughout the gene body, with an enrichment of 5hmC at the splice sites of exons to be incorporated in the mRNA transcript. Repressed genes typically contain 5mC at the enhancer, TSS, and throughout the gene body and a depletion of 5hmC.

Figure 3

A potential epigenetic role for TET proteins and DNA repair machinery in regulating neurodegeneration. TET proteins play important roles in DNA repair processes, which could be required to active DNA demethylation at neighboring DNA damage sites. Normally, TET proteins could recruit DNA repair proteins at damage sites to promote genome integrity and stability. However, TET loss of function could lead to impaired DNA repair and increased somatic mutation in brain, resulting in neurodegeneration.