Abstract
The number of children with mild neurodevelopmental disorders, such as autism, has been recently increasing in advanced countries. This increase is probably caused by environmental factors rather than genetic factors, because it is unlikely that genetic mutation rates suddenly increased within a short period. Epigenetics is a mechanism that regulates gene expression, depending not on the underlying DNA sequence but on the chemical modifications of DNA and histone proteins. Because mental stress can alter the epigenetic status in neuronal cells, environmental factors may alter brain function through epigenetic changes. However, one advantage of epigenetic changes is their reversibility. Therefore, diseases due to abnormal epigenetic regulation are theoretically treatable. In fact, several drugs for treating mental diseases are known to have restoring effects on aberrant epigenetic statuses, and a novel therapeutic strategy targeting gene has been developed. In this review, we discuss epigenetic mechanisms of congenital and acquired neurodevelopmental disorders, drugs with epigenetic effects, novel therapeutic strategies for epigenetic diseases, and future perspectives in epigenetic medicine.
Highlights
Genomic DNA is faithfully replicated and divided between two daughter cells in the course of each cell cycle
Either point mutation and deletion or a duplication results in similar disease phenotypes in various syndromes; mutations of the proteolipid protein 1 gene (PLP1) results in Pelizaeus-Merzbacher disease, a severe child onset disorder [5]; lissencephaly, a syndrome characterized by abnormal neuronal migration during fetal development, results from mutations of the lissencephaly syndrome 1 gene (LIS1) [6,7]; mutation of the peripheral myelin protein 22 gene (PMP22) causes Charcot-Marie-Tooth disease, an adult-onset neuromuscular disorder [8]; and Parkinson’s disease may results from mutation of the a-synuclein gene [9]
This finding suggests that the adverse effects of early-life stress on the DNA methylation programs may last throughout life [38], and indicates that neurodevelopmental problems may arise from epigenetic dysregulation caused by environmental factors in early life (Figure 3)
Summary
Genomic DNA is faithfully replicated and divided between two daughter cells in the course of each cell cycle. DNMTs recognize methylated CpG dinucleotides on the parent strand and methylate correlating CpG dinucleotides on the daughter strand [2]. This heritability of DNA methylation patterns, as well as histone modification patterns, is mediated by epigenetic machinery. Once CpG dinucleotides in this region is methylated, a methyl-CpG binding protein is bound to the methylated region, and recruits histone deacetylases. These proteins changes type of histone modification, leading to “closed” chromatin conformation, which prevents from binding of a transcription factor, leading to gene suppression. We take a look at the current understanding of epigenetic mechanisms of neurodevelopmental disorders, and discuss drugs with epigenetic effects, novel therapeutic strategies for epigenetic disease, and future perspectives in epigenetic medicine
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