Effect of mood stabilizers on DNA methylation in human neuroblastoma cells

Tatsuro Asai, Miki Bundo, Hiroko Sugawara, Fumiko Sunaga, Junko Ueda, Gen Tanaka, Jun Ishigooka, Kiyoto Kasai, Tadafumi Kato, Kazuya Iwamoto

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2285-2294
Number of pages10
JournalInternational Journal of Neuropsychopharmacology
Volume16
Issue number10
DOIs
StatePublished - Nov 2013
Externally publishedYes

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DNA Methylation
Neuroblastoma
Epigenomics
Brain-Derived Neurotrophic Factor
Mood Disorders
Bipolar Disorder
Lithium
Carbamazepine
Brain
Valproic Acid
Genetic Promoter Regions
Suicide
Methylation
Genes
Psychiatry

Keywords

  • BDNF
  • carbamazepine
  • lithium
  • serotonin transporter
  • valproate

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Psychiatry and Mental health

Cite this

Effect of mood stabilizers on DNA methylation in human neuroblastoma cells. / Asai, Tatsuro; Bundo, Miki; Sugawara, Hiroko; Sunaga, Fumiko; Ueda, Junko; Tanaka, Gen; Ishigooka, Jun; Kasai, Kiyoto; Kato, Tadafumi; Iwamoto, Kazuya.

In: International Journal of Neuropsychopharmacology, Vol. 16, No. 10, 11.2013, p. 2285-2294.

Research output: Contribution to journalArticle

Asai, T, Bundo, M, Sugawara, H, Sunaga, F, Ueda, J, Tanaka, G, Ishigooka, J, Kasai, K, Kato, T & Iwamoto, K 2013, 'Effect of mood stabilizers on DNA methylation in human neuroblastoma cells', International Journal of Neuropsychopharmacology, vol. 16, no. 10, pp. 2285-2294. https://doi.org/10.1017/S1461145713000710
Asai, Tatsuro ; Bundo, Miki ; Sugawara, Hiroko ; Sunaga, Fumiko ; Ueda, Junko ; Tanaka, Gen ; Ishigooka, Jun ; Kasai, Kiyoto ; Kato, Tadafumi ; Iwamoto, Kazuya. / Effect of mood stabilizers on DNA methylation in human neuroblastoma cells. In: International Journal of Neuropsychopharmacology. 2013 ; Vol. 16, No. 10. pp. 2285-2294.
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