DNA Methylation Profiling in a Neuroblastoma Cell Line Exposed to the Antipsychotic Perospirone

Yui Murata; Miki Bundo; Fumiko Sunaga; Kiyoto Kasai; Kazuya Iwamoto

doi:10.1055/s-0044-101467

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2019; 52(02): 63-69
DOI: 10.1055/s-0044-101467

Original Paper

DNA Methylation Profiling in a Neuroblastoma Cell Line Exposed to the Antipsychotic Perospirone

Yui Murata

¹Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan

²Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan

³Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto, 860-8556, Japan

,

Miki Bundo

¹Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan

³Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto, 860-8556, Japan

,

Fumiko Sunaga

¹Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan

,

Kiyoto Kasai

²Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan

,

Kazuya Iwamoto

¹Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan

³Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto, 860-8556, Japan

› Author Affiliations

Abstract

Introduction Accumulating evidence suggests the importance of epigenetic changes in the brain induced by antipsychotic drugs. However, due to the lack of systematic investigation, their effects on epigenetic status remain largely unclear. During the course of examining the epigenetic effects of antipsychotics, we here focused on perospirone, an atypical antipsychotic drug mainly used in Japan.

Methods Genomic DNA was obtained from human neuroblastoma cells exposed to 2 different doses of perospirone. Comprehensive DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip.

Results Of about 470,000 probes, perospirone exposure changed DNA methylation at 4098 probes. These probes were enriched to genes for neural development. Probes showing hypermethylation were mainly found at gene body and intergenic regions, whereas those that showed hypomethylation were located near promoter regions. Additionally, DNA methylation changes were found in the probes for dopamine receptor 2 and serotonin receptor (HTR) 2A and HTR1A, which are the pharmacological targets of atypical antipsychotics.

Discussion Our comprehensive DNA methylation analyses will contribute to a better understanding of detailed pharmacological actions of perospirone.

Key words

epigenetics - antipsychotic drug - HumanMethylation450 BeadChip - SK-N-SH cell

Full Text

References

References
1 Onrust SV, McClellan K. Perospirone. CNS Drugs 2001; 15: 329-337
2 Takekita Y, Fabbri C, Kato M. et al. Antagonist and partial agonist at the dopamine D2 receptors in drug-naive and non-drug-naive schizophrenia: A randomized, controlled trial. Eur Arch Psychiatry Clin Neurosci 2015; 265: 579-588
3 Takekita Y, Kato M, Wakeno M. et al. A 12-week randomized, open-label study of perospirone versus aripiprazole in the treatment of Japanese schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry 2013; 40: 110-114
4 Tsujino N, Nemoto T, Morita K. et al. Long-term efficacy and tolerability of perospirone for young help-seeking people at clinical high risk: A preliminary open trial. Clin Psychopharmacol Neurosci 2013; 11: 132-136
5 Higuchi Y, Sumiyoshi T, Ito T, Suzuki M. Perospirone normalized P300 and cognitive function in a case of early psychosis. J Clin Psychopharmacol 2013; 33: 263-266
6 Suzuki H, Gen K, Inoue Y. Comparison of the anti-dopamine D(2) and anti-serotonin 5-HT(2A) activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof. J Psychopharmacol 2013; 27: 396-400
7 Iwakawa M, Terao T, Soya A. et al. A novel antipsychotic, perospirone, has antiserotonergic and antidopaminergic effects in human brain: findings from neuroendocrine challenge tests. Psychopharmacology (Berl) 2004; 176: 407-411
8 Suzuki H, Gen K, Inoue Y. An unblinded comparison of the clinical and cognitive effects of switching from first-generation antipsychotics to aripiprazole, perospirone or olanzapine in patients with chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 161-168
9 Okugawa G, Kato M, Wakeno M. et al. Randomized clinical comparison of perospirone and risperidone in patients with schizophrenia: Kansai Psychiatric Multicenter Study. Psychiatry Clin Neurosci 2009; 63: 322-328
10 Swathy B, Banerjee M. Understanding epigenetics of schizophrenia in the backdrop of its antipsychotic drug therapy. Epigenomics 2017; 9: 721-736
11 Asai T, Bundo M, Sugawara H. et al. Effect of mood stabilizers on DNA methylation in human neuroblastoma cells. Int J Neuropsychopharmacol 2013; 16: 2285-2294
12 Murata Y, Nishioka M, Bundo M. et al. Comprehensive DNA methylation analysis of human neuroblastoma cells treated with blonanserin. Neurosci Lett 2014; 563: 123-128
13 Sugawara H, Bundo M, Asai T. et al. Effects of quetiapine on DNA methylation in neuroblastoma cells. Prog Neuropsychopharmacol Biol Psychiatry 2015; 56: 117-121
14 Dedeurwaerder S, Defrance M, Calonne E. et al. Evaluation of the Infinium Methylation 450K technology. Epigenomics 2011; 3: 771-784
15 Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res 2009; 37: W305-W311
16 Hulsen T, de Vlieg J, Alkema W. BioVenn - a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. BMC Genomics 2008; 9: 488
17 Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986; 321: 209-213
18 Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012; 13: 484-492
19 Lee YM, Park SH, Shin DI. et al. Oxidative modification of peroxiredoxin is associated with drug-induced apoptotic signaling in experimental models of Parkinson disease. J Biol Chem 2008; 283: 9986-9998
20 Cumming RC, Dargusch R, Fischer WH, Schubert D. Increase in expression levels and resistance to sulfhydryl oxidation of peroxiredoxin isoforms in amyloid beta-resistant nerve cells. J Biol Chem 2007; 282: 30523-30534
21 Palmfeldt J, Henningsen K, Eriksen SA. et al. Protein biomarkers of susceptibility and resilience to stress in a rat model of depression. Mol Cell Neurosci 2016; 74: 87-95
22 Li L, Zhu K, Liu Y. et al. Targeting thioredoxin-1 with siRNA exacerbates oxidative stress injury after cerebral ischemia/reperfusion in rats. Neuroscience 2015; 284: 815-823
23 Tamasi V, Petschner P, Adori C. et al. Transcriptional evidence for the role of chronic venlafaxine treatment in neurotrophic signaling and neuroplasticity including also Glutamatergic [corrected] - and insulin-mediated neuronal processes. PLoS One 2014; 9: e113662
24 Buscarlet M, Hermann R, Lo R. et al. Cofactor-activated phosphorylation is required for inhibition of cortical neuron differentiation by Groucho/TLE1. PLoS One 2009; 4: e8107
25 Buscarlet M, Perin A, Laing A. et al. Inhibition of cortical neuron differentiation by Groucho/TLE1 requires interaction with WRPW, but not Eh1, repressor peptides. J Biol Chem 2008; 283: 24881-24888
26 Yao J, Liu Y, Husain J. et al. Combinatorial expression patterns of individual TLE proteins during cell determination and differentiation suggest non-redundant functions for mammalian homologs of Drosophila Groucho. Dev Growth Differ 1998; 40: 133-146
27 Yao J, Liu Y, Lo R. et al. Disrupted development of the cerebral hemispheres in transgenic mice expressing the mammalian Groucho homologue transducin-like-enhancer of split 1 in postmitotic neurons. Mech Dev 2000; 93: 105-115
28 Zhang X, Chen HM, Jaramillo E. et al. Histone deacetylase-related protein inhibits AES-mediated neuronal cell death by direct interaction. J Neurosci Res 2008; 86: 2423-2431
29 Koch M, Veit G, Stricker S. et al. Expression of type XXIII collagen mRNA and protein. J Biol Chem 2006; 281: 21546-21557
30 Banyard J, Bao L, Hofer MD. et al. Collagen XXIII expression is associated with prostate cancer recurrence and distant metastases. Clin Cancer Res 2007; 13: 2634-2642
31 Spivey KA, Banyard J, Solis LM. et al. Collagen XXIII: a potential biomarker for the detection of primary and recurrent non-small cell lung cancer. Cancer Epidemiol Biomarkers Prev 2010; 19: 1362-1372
32 Ebstein F, Lange N, Urban S. et al. Maturation of human dendritic cells is accompanied by functional remodelling of the ubiquitin-proteasome system. Int J Biochem Cell Biol 2009; 41: 1205-1215
33 Markson G, Kiel C, Hyde R. et al. Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network. Genome Res 2009; 19: 1905-1911
34 Fagerberg L, Hallstrom BM, Oksvold P. et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics 2014; 13: 397-406