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Dynamic Regulation of DNA Methylation and Brain Functions - PubMed

  • ️Sun Jan 01 2023

Review

Dynamic Regulation of DNA Methylation and Brain Functions

Jiaxiang Xie et al. Biology (Basel). 2023.

Abstract

DNA cytosine methylation is a principal epigenetic mechanism underlying transcription during development and aging. Growing evidence suggests that DNA methylation plays a critical role in brain function, including neurogenesis, neuronal differentiation, synaptogenesis, learning, and memory. However, the mechanisms underlying aberrant DNA methylation in neurodegenerative diseases remain unclear. In this review, we provide an overview of the contribution of 5-methycytosine (5mC) and 5-hydroxylcytosine (5hmC) to brain development and aging, with a focus on the roles of dynamic 5mC and 5hmC changes in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Identification of aberrant DNA methylation sites could provide potential candidates for epigenetic-based diagnostic and therapeutic strategies for neurodegenerative diseases.

Keywords: DNA methylation; aging; development; neurodegenerative diseases; neurogenesis; transcriptional regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

DNA methylation formation and regulation in gene expression. (A) The cycle of DNA methylation. 5mC is formed from C by the catalyzation of DNMTs; then, it can be hydroxylated to 5hmC and further oxidized to 5fC and 5CaC by TET enzymes. 5fC and 5caC are recognized by thymine DNA glycosylase (TDG), which triggers the base excision repair (BER) process, leading to the conversion to unmethylated cytosine. (B) Possible role of 5mC and 5hmC in gene expression. Hypermethylated 5mC at CpG islands of gene promoters generally inhibits gene transcription (blue line). 5hmC of gene enhancers and gene bodies up-regulates gene expression (red line).

Figure 2
Figure 2

Summary of dynamic 5mC and 5hmC in development and aging and their abnormalities in neurodegenerative diseases (AD, PD, and HD). Green, hypomethylation; red, hypermethylation; dashed line, the conclusion is controversial. Different brain regions are numbered as follows: 1. substantia nigra, 2. frontal cortices, 3. temporal cortices, 4. striatum, 5. putamen, 6. cerebellum, 7. entorhinal cortex, 8. hippocampus, 9. dorsolateral prefrontal cortex, 10. middle frontal gyrus (MFG), and 11. middle temporal gyrus (MTG). Not underlined, global 5mC change; underlined, global 5hmC change.

Figure 3
Figure 3

The weight of DNA methylation, histone modifications, and telomere in the process of brain aging. A Venn diagram created by summarizing publications in the Web of Science Core Collection, Chinese Science Citation Database, KCI-Korean Journal Database, MEDLINE, and SciELO Citation Index since 1950.

Figure 4
Figure 4

Multiple roles of formaldehyde in methylation. Formaldehyde decreased DNMT1/3a expression and global DNA methylation levels. Formaldehyde also inhibited DNMT1/3a activity by modifying cystine residues. Following the injection of formaldehyde into the brains of rats and rhesus monkeys, the animals exhibited symptoms associated with AD.

Figure 5
Figure 5

Schematic diagram of L-DOPA and atremorine against MPTP-induced dopaminergic neurodegeneration. Atremorine has an antioxidant impact, including inhibition of reactive oxygen species (ROS), restoration of total ROS levels, and a significant improvement in total antioxidant capacity. Atremorine inhibits the ubiquitin-proteasome system and accumulation of α-synuclein to regulate dopamine/L-Dopa levels in the brain and exhibits neuroprotective effects. Dopamine levels can also be regulated by direct supplementation with L-DOPA.

Figure 6
Figure 6

Inhibition of DNMTs (decitabine or FdCyd) in HD neurons blocks mutant Htt-induced transcriptional repression. The full-length huntingtin is produced by translating HTT. Proteolysis cleaves native full-length huntingtin to produce extra protein fragments, which form aggregates in the nucleus and cytoplasm. Huntingtin aggregation causes global cellular impairments, such as synaptic dysfunction, mitochondrial toxicity, and decreased axonal transport. Decitabine or FdCyd, as an inhibitor of DNMTs when administered to HD neurons, prevents the transcriptional repression induced by mutant HTT.

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