Chapter 4 - The Role of DNA Methylation in the Central Nervous System and Neuropsychiatric Disorders

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DNA methylation is an epigenetic mechanism in which the methyl group is covalently coupled to the C5 position of the cytosine residue of CpG dinucleotides. DNA methylation generally leads to gene silencing and is catalyzed by a group of enzymes known as DNA methyltransferases (Dnmt). During development, the epigenome undergoes waves of demethylation and methylation changes. As a result, there are cell type/tissue-specific DNA methylation patterns. Since DNA methylation changes only happen during DNA replication to maintain methylation patterns on hemimethylated DNA or establish new methylation, Dnmt expression generally decreases greatly after cell division. However, significant levels of Dnmts were noticed specifically in postmitotic neurons, suggesting a functional importance of Dnmt in the nervous system. Accumulating evidence showed that DNA methylation correlates with certain neuropsychiatric disorders such as schizophrenia, Rett syndrome, and ICF syndrome. Studies of methyl-CpG-binding proteins, Dnmt inhibitors, and Dnmt knockout mice also explored the key role of DNA methylation in neural development, plasticity, learning, and memory. Though an enzyme exhibiting DNA demethylation capability in vertebrates still remains to be identified, DNA methylation status in the CNS appeared to be reversible at certain genomic loci. This supports a maintenance role of Dnmt to prevent active demethylation in postmitotic neurons. Taken together, DNA methylation provides an epigenetic mechanism of gene regulation in neural development, function, and disorders.

Introduction

The word “epigenetics” is normally defined as “the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence” (Bird, 2007, Jaenisch and Bird, 2003). However, given the fact that many chromatin marks are short-lived and not transmissible between generations and that DNA methylation pattern can also be rapidly removed during development, arguing for the emphasis on heritability for epigenetics may not be necessary (Bird, 2007).

DNA methylation and histone modification are the two major epigenetic mechanisms. As the fundamental unit of chromatin, the nucleosome consists of DNA wrapping around an octamer histone core. This enables DNA to be tightly packaged into the nucleus. The epigenetic mechanisms adjust gene activity by altering accessibility of DNA to the transcription machinery without changing the genetic code. While modification of DNA by methylation generally leads to gene silencing, posttranslational modifications of histone proteins including acetylation, methylation, phosphorylation, ubiquitination, or sumoylation can lead to both gene activation and repression (Jenuwein and Allis, 2001). One of the best-studied histone modifications is the acetylation status of lysine residues, a reversible process that is catalyzed by either histone acetylase (HAT) or histone deacetylase (HDAC). The addition of an acetyl group decreases the interaction between the negatively charged DNA backbone and the positively charged histone tail. This interaction can lead to a less compact nucleosome, and open access to transcription factor complexes. Conversely, HDAC removes the acetyl group, potentially leading to gene transcription repression. Methylation of histones is more complex since each distinct (mono-, di-, or tri-) methylation of different lysine residue can have opposite effects on transcription. For instance, H3 at lysine 4 (K4) is associated with transcriptional activation whereas methylations on histone H3 at K9 or K27 are usually indicative of transcriptional inhibition (Kouzarides, 2007). Moreover, methylation of histones can be reversed as well (Klose et al., 2006, Shi et al., 2004). This newly discovered mechanism for histone demethylation adds another wrinkle into the understanding of how histones regulate gene expression. It has been demonstrated that epigenetic mechanisms play pivotal roles in translating environmental stimuli into long-lasting gene expression changes in the nervous system which is required under both physiological (such as learning and memory) (Feng et al., 2007) and pathological conditions (such as psychiatric disorders) (Tsankova et al., 2007). However, most of these studies focused on histone modifications. For example, in Aplysia, histone acetylation plays a major role in excitatory transmitter activated gene expression which is needed for long-term synaptic plasticity (Guan et al., 2002). Also, the mutation of a histone acetyltransferase gene is believed to be the cause of a mental retardation disease Rubinstein–Taybi syndrome (RTS) (Petrij et al., 1995). In a histone acetyltransferase mutant RTS mouse model, either suppression of transgene expression or HDAC inhibitor administration could rescue the impairment on long-term memory stabilization (Korzus et al., 2004). More strikingly, in a mouse model of neurodegeneration, increased histone acetylation by inhibitors of HDAC could induce recovery of learning and memory (Fischer et al., 2007, Guan et al., 2009). It is believed that different histone modifications, in combination or alone, define a specific epigenetic mark (histone code) that will lead to different gene expression scenarios. For example, acute and chronic cocaine addiction induced expression of different genes which are associated with different epigenetic regulatory mechanisms (Colvis et al., 2005). The epigenetic mechanism's effect on higher neural functioning appears to be universal since some other epigenetic factors’ modulating roles were also found. For instance, KAP1, a vertebrate-specific epigenetic repressor, was found to control gene expression in the hippocampus and modulate the behavioral response to stress (Jakobsson et al., 2008). A further understanding of epigenetic mechanisms in neural functioning may advance our approaches to neuropsychiatric disorder therapies.

Not as dynamic as histone tail modification, covalent 5-cytosine methylation is deemed to be a more static mark. DNA methylation pattern maintenance or establishment only happens during DNA replication (Cameron et al., 1999, Holliday, 1999). DNA methylation normally will not change in nondividing cells which makes DNA methylation a less prominent candidate for dynamic gene expression regulation within postmitotic neurons. However, recent findings support important functional roles of DNA methylation in the nervous system. Since the function of histone modification in the nervous system has been well reviewed (Colvis et al., 2005, Tsankova et al., 2007), we will focus on the role of DNA methylation in this chapter.

Section snippets

DNA Methylation and DNA Methyltransferase

Methylation of DNA at the fifth carbon of the cytosine ring exists in all vertebrates, fungi, flowering plants, and some invertebrate insects as well as certain bacterial species. The biological functions of cytosine methylation are quite different in prokaryotes and eukaryotes. In prokaryotes, DNA methylation occurs at adenine as well as cytosine bases, playing a central role in the host restriction system. In eukaryotes, DNA methylation is restricted to cytosine bases and is coupled with a

DNA Methylation Mediates Gene Silencing

During development, the epigenome undergoes waves of demethylation and methylation change. As a result, various cell type/tissue-specific DNA methylation patterns occur at specific times. Global de novo methylation happens specifically during germ cell development and early embryogenesis. How Dnmt enzymes are recruited to the DNA to pursue DNA methylation modification is still unclear. Recent studies suggest there are at least three possible means. First, Dnmt3 enzymes themselves may target DNA

Role of DNA Methylation in the CNS and Neuropsychiatric Disorders

Epigenetic mechanisms, which include histone modification and DNA methylation, are believed to adjust the chromatin remodeling and accessibility of gene promoters (Jaenisch and Bird, 2003) to regulate neural adaptive gene expression. The essential roles of histone modification have been well demonstrated (Tsankova et al., 2007). Different histone modifications, in combination or alone, define a specific epigenetic mark (histone code) that leads to different gene expression scenarios (Colvis et

Conclusion Remarks

DNA methylation provides an epigenetic means of neural gene expression regulation. In the past decade or so, the pivotal roles of DNA methylation as well as Dnmts in the CNS have been recognized in neural differentiation, cell survival, cell maturation, neural plasticity, as well as some neuropsychiatric disorders. However, a definitive function of Dnmt in the postmitotic neurons is still elusive. An active DNA methylation turnover in the neuronal cells also needs to be confirmed. In the

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