CpG and Non-CpG Methylation in Epigenetic Gene Regulation and Brain Function

Abstract

DNA methylation is a major epigenetic mark with important roles in genetic regulation. Methylated cytosines are found primarily at CpG dinucleotides, but are also found at non-CpG sites (CpA, CpT, and CpC). The general functions of CpG and non-CpG methylation include gene silencing or activation depending on the methylated regions. CpG and non-CpG methylation are found throughout the whole genome, including repetitive sequences, enhancers, promoters, and gene bodies. Interestingly, however, non-CpG methylation is restricted to specific cell types, such as pluripotent stem cells, oocytes, neurons, and glial cells. Thus, accumulation of methylation at non-CpG sites and CpG sites in neurons seems to be involved in development and disease etiology. Here, we provide an overview of CpG and non-CpG methylation and their roles in neurological diseases.

Keywords: CpG methylation; epigenetics; non-CpG methylation.

Figure 1

DNA methylation and demethylation. (A) DNA methylation occurs at the fifth carbon of cytosine and leads to the formation of 5-methylcytosine (5mC); (B) DNA methylation is predominantly found at CpG sites, and is much less commonly observed at non-CpG sites, such as CpA, CpT, and CpC; and (C) 5mC can be demethylated by passive or active processes. Active DNA demethylation can occur either via oxidation or deamination. The oxidation process is carried out by Ten-Eleven-Translocation (TET) proteins, including TET1, TET2, and TET3. TETs convert 5mC into 5-hydroxymethylcytosine (5hmC), which is further changed into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5caC is excised and replaced via base excision repair. 5mC and 5hmC can also be demethylated via deamination by activation induced cytidine deaminase (AID)/apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC).

Figure 2

Non-CpG methylation levels in different cell types during differentiation of human ES cells. (A) Tissue-specific non-CpG methylation levels. In mammalian somatic cells, neurons have the highest non-CpG methylation levels, although non-CpG methylation is rare in most other differentiated cell types, such as fibroblasts. Non-CpG methylation is also enriched in ES cells. The human male ES cell line (H1) is more highly methylated than the female ES cell line (H9); (B) Dynamics of non-CpG methylation levels during the differentiation of ES cells. Non-CpG methylation levels decrease when ES cells differentiate into neural progenitor cells (NPCs). When NPCs are further differentiated into neurons and glial cells, non-CpG methylation is increased again. Interestingly, non-CpG methylation levels are higher in neurons than in glial cells.