Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects
Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects
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DOI：
10.1001/archgenpsychiatry.2010.9
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发表时间：
2010-03-01
影响因子：
--
通讯作者：
Chiariotti, Lorenzo
中科院分区：
文献类型：
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作者：
Keller, Simona;Sarchiapone, Marco;Chiariotti, Lorenzo
内容：脑源性神经营养因子（BDNF）在自杀行为的病理生理学中起着关键作用，自杀者脑和血浆中BDNF水平降低。到目前为止，导致BDNF表达下调的机制知之甚少。Objectives：To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects.Design：Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF信使RNA水平测定定量实时聚合酶链反应。设置：学术医疗中心。患者或其他参与者：四十四自杀完成者和33个非自杀对照组的白色种族。主要结局指标：在BDNF启动子IV和全基因组DNA甲基化水平在大脑的Wernicke area.Results：自杀受试者的尸检大脑样本中的DNA甲基化程度显示了一个统计学显着增加在特定的CpG位点的BDNF启动子外显子IV相比，非自杀对照组（P.001）。位于两条链上-300 500区域的大多数CpG位点具有低甲基化或无甲基化，除了位于转录起始位点附近的少数位点具有差异甲基化，而受试者之间的全基因组甲基化水平相当。在33名非自杀对照受试者中，通过焦磷酸测序分析的4个CpG位点的平均甲基化程度始终低于12.9%，而在44名自杀受害者中的13名（30%）中，平均甲基化程度介于13.1%和34.2%之间。较高的甲基化程度对应于较低的BDNF信使RNA levels.Conclusions：BDNF启动子/外显子IV是经常高甲基化的Wernicke区的自杀受试者的死后大脑，无论全基因组甲基化水平，表明基因特异性的DNA甲基化的增加可能会导致或有助于自杀受试者的BDNF表达下调。报告的数据揭示了大脑表观遗传改变和自杀行为之间的新联系。
Context: Brain-derived neurotrophic factor (BDNF) plays pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood.Objectives: To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects.Design: Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction.Setting: Academic medical center.Patients or Other Participants: Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity. Main Outcome Measures: The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area.Results: Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter exon IV compared with nonsuicide control subjects (P.001). Most of the CpG sites lying in the -300 500 region, on both strands, had low or no methylation, with the exception of a few sites located near the transcriptional start site that had differential methylation,while genome-wide methylation levels were comparable among the subjects. The mean methylation degree at the 4 CpG sites analyzed by pyrosequencing was always less than 12.9% in the 33 nonsuicide control subjects, while in 13 of 44 suicide victims (30%), the mean methylation degree ranged between 13.1% and 34.2%. Higher methylation degree corresponded to lower BDNF messenger RNA levels.Conclusions: BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.