Effect of mood stabilizers on DNA methylation in human neuroblastoma cells

Abstract

Unraveling the epigenetic status of neuronal cells in the brain is critical to our understanding of the pathophysiology of psychiatric disorders, which may reflect a complex interaction between genetic and environmental factors. Several epigenetic studies of mood disorders have been conducted with postmortem brains. However, proper interpretation of the results is hampered by our scant understanding of the effects of mood stabilizers on the epigenetic status of neuronal cells. We performed both comprehensive and gene-specific analyses to examine DNA methylation in human neuroblastoma SK-N-SH cells treated with three mood stabilizers: lithium, valproate and carbamazepine. Measurement of the level of DNA methylation of about 27 000 CpG sites revealed a profound epigenetic effect of lithium, compared with the two other mood stabilizers. In addition, we found that the mood stabilizers have common epigenetic targets and a propensity to increase DNA methylation. Gene-specific analysis involved detailed analysis of the methylation of promoter regions of SLC6A4 and BDNF, both of which have been reported to show altered DNA methylation in bipolar disorder patients or suicide victims, by extensive bisulfite sequencing. We did not observe significant changes in DNA methylation at BDNF promoter IV. However, we found that CpG sites of SLC6A4, which were hypermethylated in patients with bipolar disorder, were hypomethylated in the neuroblastoma cells treated with mood stabilizers. Our results will contribute to a better understanding of the epigenetic changes associated with mood disorders, and they also provide new insight into the mechanisms of action of mood stabilizers.

Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression

“…While such discrepancies between studies may likely reflect the heterogeneity of clinical phenotypes and underlying etiologies [1], there is also evidence for potential pharmacotherapy-related effects. For instance, Asai et al [45] identified a diverse pattern of carbamazepine-induced CpG hypermethylations and hypomethylations. Among these, we found no overlap with our candidate CpGs.…”

Decreased global methylation in patients with bipolar disorder who respond to lithium

“…Decreased levels of GSH and changes in glutathione peroxidase (GPx) activity were found in patients with BD (Andreazza et al, 2007b;Gawryluk et al, 2011;Gigante et al, 2011b;Fraguas et al, 2012). Lithium has been shown to decrease oxidative damage and increase GSH in cerebral cortex cell culture (Shao et al, 2005(Shao et al, , 2008Cui et al, 2007) as well as regulating methylation (Asai et al, 2013). D' Addario et al (2012) of reported hypomethylation in post-mortem brain tissue in patients with BD who were on lithium treatment.…”

Mood Stabilizers and the Influence on Global Leukocyte DNA Methylation in Bipolar Disorder

“…Several findings have shown that VPA affects DNA methylation in vitro [13]. We tested whether VPA treatment influenced the DNA methylation levels in bipolar patients by comparing group I (Li-mono) and group II (Li + VPA).…”

“…In addition, there are in vitro studies suggesting that VPA may lead to altered DNA methylation [23], which may be a consequence of the strong link between histone modifications and DNA methylation [7]. In neuroblastoma cell lines, VPA had the potential to lead to both hypermethylation and hypomethylation at specific gene sites, with a tendency to an overall shift towards hypermethylation [13]. Similarly, VPA increased global DNA methylation in neuroblastoma cell lines.…”

“…Some previous in vitro studies in neuroblastoma cell lines suggested that VPA treatment is associated with global hypermethylation [11,12,13]. Further, Huzayyin et al [14] reported decreased global methylation in lymphoblast cell lines from lithium-treated bipolar patients who responded well to Li compared to healthy controls.…”