Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Denmark.
Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
Neurosci Lett. 2019 Jun 21;704:145-152. doi: 10.1016/j.neulet.2019.04.015. Epub 2019 Apr 8.
The CHRNA7 gene encoding the α7 nicotinic acetylcholine receptor (nAChR) has repeatedly been linked with schizophrenia and the P50 sensory gating deficit. The α7 nAChR is considered a promising drug target for treatment of cognitive dysfunction in schizophrenia and improves memory and executive functions in patients and healthy individuals. However, clinical trials with pro-cognitive drugs are challenged by large inter-individual response variations and these have been linked to genotypic variations reducing CHRNA7 expression and α7 nAChR function. Genetic variants as well as environmental conditions may cause epigenetic dysregulation and it has previously been found that DNA methylation of a region surrounding the transcription start site of CHRNA7 is important for tissue specific regulation and gene silencing. In the present study we identify two additional regions involved in epigenetic regulation of the CHRNA7 promoter. In human temporal cortex we find large variations in expression of CHRNA7 and establish evidence for a significant correlation with DNA methylation levels of one region. We then establish evidence that genotypic variations can influence methylation levels of the CHRNA7 promoter. Epigenetic dysregulation can be reversed by pharmacological intervention and in HeLa cells. Valproate, a commonly used mood stabiliser, caused demethylation and increased CHRNA7 expression in HeLA cells. Similar demethylation effect and increased CHRNA7 expression was obtained in SH-SY5Y cells stimulated concomitantly with valproate and nicotine. In summary, both genetic and epigenetic information could be useful to predict treatment outcomes in patients and epigenetic modulation may serve as a mechanism for potentiating the effects of α7 nAChR agonists.
CHRNA7 基因编码α7 型烟碱型乙酰胆碱受体（nAChR），该基因与精神分裂症和 P50 感觉门控缺陷反复相关。α7 nAChR 被认为是治疗精神分裂症认知功能障碍的有前途的药物靶点，可改善患者和健康个体的记忆和执行功能。然而，具有认知增强作用的药物临床试验受到个体间反应差异大的挑战，这些差异与降低 CHRNA7 表达和α7 nAChR 功能的基因型变异有关。遗传变异以及环境条件可能导致表观遗传失调，先前已经发现 CHRNA7 转录起始位点周围区域的 DNA 甲基化对于组织特异性调节和基因沉默很重要。在本研究中，我们确定了另外两个参与 CHRNA7 启动子表观遗传调控的区域。在人类颞叶皮层中，我们发现 CHRNA7 的表达存在很大差异，并建立了证据表明与一个区域的 DNA 甲基化水平具有显著相关性。然后，我们建立了证据表明，基因型变异可以影响 CHRNA7 启动子的甲基化水平。表观遗传失调可以通过药理学干预在 HeLa 细胞中逆转。丙戊酸钠是一种常用的情绪稳定剂，可引起 HeLa 细胞中的去甲基化和 CHRNA7 表达增加。在同时用丙戊酸钠和尼古丁刺激的 SH-SY5Y 细胞中也获得了类似的去甲基化作用和 CHRNA7 表达增加。总之，遗传和表观遗传信息都可能有助于预测患者的治疗效果，而表观遗传调节可能是增强α7 nAChR 激动剂作用的机制。
