Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Saitama, Japan.
Mol Psychiatry. 2021 Jul;26(7):3407-3418. doi: 10.1038/s41380-021-01079-0. Epub 2021 Apr 20.
Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed promoter-wide DNA methylation analysis of neuronal and nonneuronal nuclei in the prefrontal cortex of patients with BD (N = 34) and controls (N = 35). We found decreased DNA methylation at promoters in both cell types in the BD patients. Gene Ontology (GO) analysis of differentially methylated region (DMR)-associated genes revealed enrichment of molecular motor-related genes in neurons, chemokines in both cell types, and ion channel- and transporter-related genes in nonneurons. Detailed GO analysis further revealed that growth cone- and dendrite-related genes, including NTRK2 and GRIN1, were hypermethylated in neurons of BD patients. To assess the effect of medication, neuroblastoma cells were cultured under therapeutic concentrations of three mood stabilizers. We observed that up to 37.9% of DMRs detected in BD overlapped with mood stabilizer-induced DMRs. Interestingly, mood stabilizer-induced DMRs showed the opposite direction of changes in DMRs, suggesting the therapeutic effects of mood stabilizers. Among the DMRs, 12 overlapped with loci identified in a genome-wide association study (GWAS) of BD. We also found significant enrichment of neuronal DMRs in the loci reported in another GWAS of BD. Finally, we performed qPCR of DNA methylation-related genes and found that DNMT3B was overexpressed in BD. The cell-type-specific DMRs identified in this study will be useful for understanding the pathophysiology of BD.
双相情感障碍（BD）是一种严重的精神障碍，其特征是反复出现情绪波动。尽管遗传因素与 BD 的病因学有关，但潜在的分子机制，特别是环境因素如何影响大脑，仍知之甚少。我们对 BD 患者（N=34）和对照组（N=35）的前额叶神经元核和非神经元核进行了全启动子 DNA 甲基化分析。我们发现 BD 患者两种细胞类型的启动子 DNA 甲基化程度降低。差异甲基化区域（DMR）相关基因的基因本体论（GO）分析显示，神经元中与分子马达相关的基因、两种细胞类型中的趋化因子以及非神经元中与离子通道和转运体相关的基因富集。详细的 GO 分析进一步表明，神经元中包括 NTRK2 和 GRIN1 在内的生长锥和树突相关基因发生了过度甲基化。为了评估药物的作用，我们在三种心境稳定剂的治疗浓度下培养神经母细胞瘤细胞。我们发现，BD 患者中检测到的高达 37.9%的 DMR 与心境稳定剂诱导的 DMR 重叠。有趣的是，心境稳定剂诱导的 DMR 改变的方向与 DMR 相反，提示心境稳定剂的治疗效果。在 DMR 中，有 12 个与 BD 的全基因组关联研究（GWAS）中鉴定的基因座重叠。我们还发现，BD 的另一个 GWAS 中报告的基因座中神经元 DMR 显著富集。最后，我们对 DNA 甲基化相关基因进行了 qPCR 检测，发现 BD 中 DNMT3B 表达过度。本研究中鉴定的细胞类型特异性 DMR 将有助于理解 BD 的病理生理学。
