Kikuchi Masataka, Nakazawa Takanobu, Kinoshita Makoto, Yamamori Hidenaga, Yasuda Yuka, Fujimoto Michiko, Hashimoto Ryota, Numata Shusuke
Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Bioscience, Tokyo University of Agriculture, Tokyo, Japan.
Front Psychiatry. 2021 Sep 20;12:734606. doi: 10.3389/fpsyt.2021.734606. eCollection 2021.
Schizophrenia is a mental illness that involves both genetic and environmental factors. Clozapine, an atypical antipsychotic, is a well-established therapy for treatment-resistant schizophrenia. In this study, we focused on a set of monozygotic twins with treatment-resistant schizophrenia in which one twin effectively responded to clozapine treatment and the other did not. Our previous study generated neurons from induced pluripotent stem (iPS) cells derived from these patients and compared the transcriptome profiles between mock- and clozapine-treated neurons. In this study, we performed genome-wide DNA methylation profiling to investigate the mechanisms underlying gene expression changes. First, we extracted the differentially methylated sites from each twin based on statistical analysis. Then, we combined the DNA methylation profiling with transcriptome profiling from our previous RNA-seq data. Among the genes with altered methylation and expression, we found the different proportions of the genes related to neuronal and synaptic functions between the clozapine responder and non-responder (35.7 and 6.7%, respectively). This trend was observed even when the basal differences between the responder and non-responder was excluded. These results suggest that effective clozapine action may correct the abnormalities of neuronal and synapse functions in schizophrenia via changes in methylation.
精神分裂症是一种涉及遗传和环境因素的精神疾病。氯氮平作为一种非典型抗精神病药物，是治疗难治性精神分裂症的一种成熟疗法。在本研究中，我们聚焦于一组患有难治性精神分裂症的同卵双胞胎，其中一个双胞胎对氯氮平治疗有效，而另一个则无效。我们之前的研究从这些患者的诱导多能干细胞（iPS细胞）中生成神经元，并比较了模拟处理和氯氮平处理的神经元之间的转录组图谱。在本研究中，我们进行了全基因组DNA甲基化分析，以研究基因表达变化背后的机制。首先，我们基于统计分析从每个双胞胎中提取差异甲基化位点。然后，我们将DNA甲基化分析与我们之前RNA测序数据中的转录组分析相结合。在甲基化和表达发生改变的基因中，我们发现氯氮平反应者和非反应者中与神经元和突触功能相关的基因比例不同（分别为35.7%和6.7%）。即使排除反应者和非反应者之间的基础差异，这种趋势仍然存在。这些结果表明，氯氮平的有效作用可能通过甲基化变化纠正精神分裂症中神经元和突触功能的异常。
