Effect of mood stabilizers on DNA methylation in human neuroblastoma cells.
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.
Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Tatsuro
T
Asai
Miki
M
Bundo
Hiroko
H
Sugawara
Fumiko
F
Sunaga
Junko
J
Ueda
Gen
G
Tanaka
Jun
J
Ishigooka
Kiyoto
K
Kasai
Tadafumi
T
Kato
Kazuya
K
Iwamoto
D018692:Antimanic Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002220:Carbamazepine / Q000494:pharmacology; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018020:Lithium Compounds / Q000494:pharmacology; D009447:Neuroblastoma / Q000235:genetics*; D011401:Promoter Regions, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology
D018692:Antimanic Agents; D019208:Brain-Derived Neurotrophic Factor; D018020:Lithium Compounds; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D002220:Carbamazepine; D014635:Valproic Acid; C579455:BDNF protein, human