DNA methylation and its basic function

Abstract

In the mammalian genome, DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine. DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA. During development, the pattern of DNA methylation in the genome changes as a result of a dynamic process involving both de novo DNA methylation and demethylation. As a consequence, differentiated cells develop a stable and unique DNA methylation pattern that regulates tissue-specific gene transcription. In this chapter, we will review the process of DNA methylation and demethylation in the nervous system. We will describe the DNA (de)methylation machinery and its association with other epigenetic mechanisms such as histone modifications and noncoding RNAs. Intriguingly, postmitotic neurons still express DNA methyltransferases and components involved in DNA demethylation. Moreover, neuronal activity can modulate their pattern of DNA methylation in response to physiological and environmental stimuli. The precise regulation of DNA methylation is essential for normal cognitive function. Indeed, when DNA methylation is altered as a result of developmental mutations or environmental risk factors, such as drug exposure and neural injury, mental impairment is a common side effect. The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.

Figure 1

DNA methylation pathways. A family of DNA methyltransferases (Dnmts) catalyzes the transfer of a methyl group from S-adenyl methionine (SAM) to the fifth carbon of cytosine residue to form 5-methylcytosine (5mC). (a) Dnmt3a and Dnmt3b are the de novo Dnmts and transfer methyl groups (red) onto naked DNA. (b) Dnmt1 is the maintenance Dnmt and maintains DNA methylation pattern during replication. When DNA undergoes semiconservative replication, the parental DNA stand retains the original DNA methylation pattern (gray). Dnmt1 associates at the replication foci and precisely replicates the original DNA methylation pattern by adding methyl groups (red) onto the newly formed daughter strand (blue).

Figure 2

Active DNA demethylation pathways. 5-Methylcytosine (5mC) can be chemically modified at two sites: the amine group and the methyl group. The amine group of 5mC can be deaminated (green) by AID/APOBEC, converting 5mC into thymine (Thy). The methyl group of 5mC can be modified by the addition of a hydroxyl group mediated by Tet enzymes to generate 5-hydroxymethyl-cytosine (5hmC). 5hmC can also be chemically modified at two sites: the amine group and the hydroxymethyl group. AID/APOBEC can deaminate (green) 5hmC to produce 5-hydroxymethyl-uracil (5hmU). In another chemical pathway for 5hmC is that Tet can further oxidize (yellow) 5hmC to form 5-formyl-cytosine (5fC) and then 5-carboxy-cytosine (5caC). Eventually, the products of each pathway—Thy, 5hmU, 5fC, and 5caC—are recognized and cleaved off to replace with a naked cytosine mediated by TDG and/or SMUG1, both components of the base excision repair pathway (red).

Figure 3

Epigenetic crosstalk. Transcription is ultimately regulated by the interaction of multiple epigenetic mechanisms that cooperate to activate or silence gene expression. Methylation is regulated by proteins such as Dnmt and Tet (purple) that are involved in the active addition or chemical modification (such as hydroxymethylation in red) of DNA methylation. To suppress gene expression, Dnmts target CpG sites and actively methylate DNA. For some Dnmts, their catalytic activity is enhanced by association with histone tails and with Dnmt3L. DNA methylation is recognized by methyl-binding proteins such as MBDs (yellow) that along with Dnmts recruit enzymes that modify the histone tails (orange) including histone deacetylases (HDACs), which remove acetylation (red), and histone methyltransferases (HMTs), which methylate histones (green) and in conjunction with DNA methylation serve to further repress gene expression. In regions of DNA with activate transcription, Tet removes DNA methylation, and histone tails in this region often contain H3K4me³ that inhibits Dnmt binding to unmethylated CpG sites and maintains a permissive environment for transcription.