Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien County, Taiwan; Department of Long-Term Care, University of Kang Ning, Taipei City, Taiwan.
Department of Psychiatry, Mackay Medical College, New Taipei City, Taiwan; Department of Psychiatry, Mackay Memorial Hospital, Taitung Branch, Taitung County, Taiwan.
Psychiatry Res. 2019 May;275:276-282. doi: 10.1016/j.psychres.2019.03.044. Epub 2019 Mar 26.
EGR1, involved in the regulation of synaptic plasticity, learning, and memory, is considered a candidate gene for schizophrenia. We resequenced the exonic regions of EGR1 in 516 patients with schizophrenia and conducted a reporter gene assay. We found two mutations including a rare mutation (c.-8C>T, rs561524195) and one common SNP (c.308-42C>T, rs11743810). The reporter gene assay showed c.-8C>T mutant did not affect promoter activity. Gene expression analyses showed that the average EGR1 mRNA and protein levels in lymphoblastoid cell lines of schizophrenia in male, but not female, were significantly higher than those in controls. We conducted in vitro DNA methylation reaction, luciferase activity assay, and pyrosequencing to assess DNA methylation of EGR1 expression underlying the pathophysiology of schizophrenia. DNA methylation of the EGR1 promoter region attenuated reporter activity, suggesting that DNA methylation regulates EGR1 expression. There were no statistically significant differences in DNA methylation levels of 17 CpG sites at the EGR1 promoter region between 64 patients with schizophrenia compared with 64 controls. These results suggest that the exonic mutations in EGR1 and DNA methylation regulating EGR1 expression might not be associated with schizophrenia. However, the gender-specific association of elevated EGR1 expression might be involved in the pathophysiology of schizophrenia.
EGR1 参与调节突触可塑性、学习和记忆，被认为是精神分裂症的候选基因。我们对 516 名精神分裂症患者的 EGR1 外显子区域进行了重测序，并进行了报告基因检测。我们发现了两种突变，包括一种罕见突变（c.-8C>T，rs561524195）和一种常见 SNP（c.308-42C>T，rs11743810）。报告基因检测表明 c.-8C>T 突变不影响启动子活性。基因表达分析表明，男性而非女性精神分裂症淋巴母细胞系的 EGR1 mRNA 和蛋白水平平均显著高于对照组。我们进行了体外 DNA 甲基化反应、荧光素酶活性测定和焦磷酸测序，以评估 EGR1 表达的 DNA 甲基化在精神分裂症发病机制中的作用。EGR1 启动子区域的 DNA 甲基化减弱了报告基因的活性，表明 DNA 甲基化调节 EGR1 表达。在 64 名精神分裂症患者和 64 名对照者的 EGR1 启动子区域的 17 个 CpG 位点的 DNA 甲基化水平没有统计学上的显著差异。这些结果表明，EGR1 的外显子突变和调节 EGR1 表达的 DNA 甲基化可能与精神分裂症无关。然而，EGR1 表达升高的性别特异性关联可能与精神分裂症的发病机制有关。
