The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

Abstract

Bipolar disorder (BD) is a multifactorial illness thought to result from an interaction between genetic susceptibility and environmental stimuli. Epigenetic mechanisms, including DNA methylation, can modulate gene expression in response to the environment, and therefore might account for part of the heritability reported for BD. This paper aims to review evidence of the potential role of DNA methylation in the pathophysiology and treatment of BD. In summary, several studies suggest that alterations in DNA methylation may play an important role in the dysregulation of gene expression in BD, and some actually suggest their potential use as biomarkers to improve diagnosis, prognosis, and assessment of response to treatment. This is also supported by reports of alterations in the levels of DNA methyltransferases in patients and in the mechanism of action of classical mood stabilizers. In this sense, targeting specific alterations in DNA methylation represents exciting new treatment possibilities for BD, and the 'plastic' characteristic of DNA methylation accounts for a promising possibility of restoring environment-induced modifications in patients.

Keywords: Bipolar disorder; DNA methylation; DNA methyltransferase; Depression; Epigenetics; Mood disorders; Mood stabilizers.

Figure 1

Catalysis of DNA methylation and hydroxylation. A) Cytosine at CpG dinucleotides can be methylated at carbon-5 by DNMTs, which use SAM as methyl-carrier, generating a modified nucleotide called 5-methylcytosine (5mC). B) Possibly as first step of an active demethylation process, 5mC can be oxidized by TET enzymes to 5-hydroxymethylcytosines (5hmC), whose exact function is still unknown. DNMT – DNA methyltransferase; TET – ten-eleven translocation.

Figure 2

Typical dynamics of DNA methylation. DNA methylation patterns are determined by a combination of genetic background and environmental exposure. By means of modulating the activity of DNMTs, CpG dinucleotides will undergo methylation or (passive) demethylation of promoters, gene bodies and/or gene regulatory regions. Hypermethylation of CGIs in promoter regions have been traditionally associated with decreased gene expression, whereas their hypomethylation has been linked to increased gene expression. DNMT – DNA methyltransferase; CGI – CpG island.