Comprehensive DNA Methylation Analysis of Human Neuroblastoma Cells Treated With Haloperidol and Risperidone.

Jianbin Du,Miki Bundo,Shinya Fujii,Kiyoto Kasai,Tomoki Kiyono,Yutaka Nakachi,Kazuya Iwamoto

doi:10.3389/fnmol.2021.792874

Abstract

Accumulating evidence suggests that the epigenetic alterations induced by antipsychotics contribute to the therapeutic efficacy. However, global and site-specific epigenetic changes by antipsychotics and those shared by different classes of antipsychotics remain poorly understood. We conducted a comprehensive DNA methylation analysis of human neuroblastoma cells cultured with antipsychotics. The cells were cultured with low and high concentrations of haloperidol or risperidone for 8 days. DNA methylation assay was performed with the Illumina HumanMethylation450 BeadChip. We found that both haloperidol and risperidone tended to cause hypermethylation changes and showed similar DNA methylation changes closely related to neuronal functions. A total of 294 differentially methylated probes (DMPs), including 197 hypermethylated and 97 hypomethylated DMPs, were identified with both haloperidol and risperidone treatment. Gene ontology analysis of the hypermethylated probe-associated genes showed enrichment of genes related to the regulation of neurotransmitter receptor activity and lipoprotein lipase activity. Pathway analysis identified that among the DMP-associated genes, SHANK1 and SHANK2 were the major genes in the neuropsychiatric disorder-related pathways. Our data would be valuable for understanding the mechanisms of action of antipsychotics from an epigenetic viewpoint.

Highlights

Schizophrenia is a major psychiatric disorder characterized by positive and negative symptoms as well as cognitive impairments
We comprehensively examined DNA methylation changes induced by a typical antipsychotic, haloperidol, and a secondgeneration atypical antipsychotic, risperidone
To the best of our knowledge, this is the first study to examine the common effect of two distinctive antipsychotics on DNA methylation in human neuroblastoma cells

Summary

Introduction

Schizophrenia is a major psychiatric disorder characterized by positive and negative symptoms as well as cognitive impairments. Genetic factors are involved in the etiology of schizophrenia, genes with large effect sizes have not been identified. In addition to the complex gene–environment interactions, recent genetic studies suggest that multiple genetic factors with small effect sizes are involved in its etiology (Purcell et al, 2009, 2014; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). Altered epigenetic status has been proposed to be involved in the pathophysiology of major psychiatric disorders, including schizophrenia (Nishioka et al, 2012; Nestler et al, 2016; Richetto and Meyer, 2020; Bundo et al, 2021; Ueda et al, 2021)

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