Comprehensive DNA methylation analysis of human neuroblastoma cells treated with blonanserin.
Blonanserin is a second-generation antipsychotic drug for schizophrenia. The pharmacological actions of blonanserin are shown to be the antagonism of dopamine receptor 2 and serotonin receptors. However, its molecular mechanisms in brain cells have not been fully characterized. Accumulating evidence suggests that antipsychotic drugs and mood stabilizers show epigenetic effects on a wide range of genes in animal and cellular models. We performed genome-wide DNA methylation analysis targeting 479,814 CpG sites of cultured human neuroblastoma cells administered with blonanserin. We found that 3,057 CpG sites showed statistically significant changes in DNA methylation at two different doses of blonanserin (1.36 nM and 13.6 nM). These included hypermethylated CpG sites that were enriched in genes related to axonogenesis and cell morphogenesis involved in neuron differentiation. We also showed that the global effect on DNA methylome depends on the concentration of the drug. With a high dose of blonanserin, the overall methylation levels across all CpG sites significantly increased. These increases in DNA methylation were prominent in the CpG sites distant from promoter regions. We further examined DNA methylation changes in specific genes implicated for the actions of antipsychotic drugs, such as the dopamine receptor 2 (DRD2) gene and the serotonin receptor 2A (HTR2A) gene. We observed that CpG sites that were located within DRD2 and HTR2A genes were significantly hypermethylated by blonanserin. The DNA methylation changes induced by the treatment with blonanserin will be useful for understanding its pharmacological actions at the cellular level.
Department of Molecular Psychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Yui
Y
Murata
Department of Molecular Psychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Masaki
M
Nishioka
Department of Molecular Psychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Miki
M
Bundo
Department of Molecular Psychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Fumiko
F
Sunaga
Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Kiyoto
K
Kasai
Department of Molecular Psychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: kaziwamoto-tky@umin.ac.jp.
Kazuya
K
Iwamoto
D014150:Antipsychotic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D015894:Genome, Human; D006801:Humans; D009447:Neuroblastoma; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*
D014150:Antipsychotic Agents; D010879:Piperazines; D010880:Piperidines; C079310:blonanserin
Antipsychotic drug; Blonanserin; DNA methylation; Human neuroblastoma cell