Labonté Benoit, Suderman Matt, Maussion Gilles, Navaro Luis, Yerko Volodymyr, Mahar Ian, Bureau Alexandre, Mechawar Naguib, Szyf Moshe, Meaney Michael J, Turecki Gustavo
McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada.
Arch Gen Psychiatry. 2012 Jul;69(7):722-31. doi: 10.1001/archgenpsychiatry.2011.2287.
Our genome adapts to environmental influences, in part through epigenetic mechanisms, including DNA methylation. Variations in the quality of the early environment are associated with alterations in DNA methylation in rodents, and recent data suggest similar processes in humans in response to early-life adversity.
To determine genome-wide DNA methylation alterations induced by early-life trauma.
Genome-wide study of promoter methylation in individuals with severe abuse during childhood. PATIENTS, SETTING, AND MAIN OUTCOME MEASURES: Promoter DNA methylation levels were profiled using methylated DNA immunoprecipitation followed by microarray hybridization in hippocampal tissue from 41 French-Canadian men (25 with a history of severe childhood abuse and 16 control subjects). Methylation profiles were compared with corresponding genome-wide gene expression profiles obtained by messenger RNA microarrays. Methylation differences between groups were validated on neuronal and nonneuronal DNA fractions isolated by fluorescence-assisted cell sorting. Functional consequences of site-specific promoter methylation were assessed by luciferase assays.
We identified 362 differentially methylated promoters in individuals with a history of abuse compared with controls. Among these promoters, 248 showed hypermethylation and 114 demonstrated hypomethylation. Validation and site-specific quantification of DNA methylation in the 5 most hypermethylated gene promoters indicated that methylation differences occurred mainly in the neuronal cellular fraction. Genes involved in cellular/neuronal plasticity were among the most significantly differentially methylated, and, among these, Alsin (ALS2) was the most significant finding. Methylated ALS2 constructs mimicking the methylation state in samples from abused suicide completers showed decreased promoter transcriptional activity associated with decreased hippocampal expression of ALS2 variants.
Childhood adversity is associated with epigenetic alterations in the promoters of several genes in hippocampal neurons.
我们的基因组会部分通过表观遗传机制（包括DNA甲基化）来适应环境影响。早期环境质量的变化与啮齿动物DNA甲基化的改变有关，最近的数据表明人类在应对早期生活逆境时也有类似过程。
确定早期生活创伤引起的全基因组DNA甲基化改变。
对童年期遭受严重虐待个体的启动子甲基化进行全基因组研究。
患者、研究地点及主要观察指标：使用甲基化DNA免疫沉淀法，随后在41名法裔加拿大男性（25名有童年期严重虐待史，16名对照受试者）的海马组织中进行微阵列杂交，对启动子DNA甲基化水平进行分析。将甲基化谱与通过信使RNA微阵列获得的相应全基因组基因表达谱进行比较。通过荧光辅助细胞分选分离的神经元和非神经元DNA组分，对组间甲基化差异进行验证。通过荧光素酶测定评估位点特异性启动子甲基化的功能后果。
与对照组相比，我们在有虐待史的个体中鉴定出362个差异甲基化的启动子。在这些启动子中，248个显示高甲基化，114个显示低甲基化。对5个甲基化程度最高的基因启动子中的DNA甲基化进行验证和位点特异性定量分析表明，甲基化差异主要发生在神经元细胞组分中。参与细胞/神经元可塑性的基因是甲基化差异最显著的基因之一，其中阿尔辛（ALS2）是最显著的发现。模仿受虐自杀完成者样本中甲基化状态的甲基化ALS2构建体显示启动子转录活性降低，与海马中ALS2变体表达降低相关。
童年期逆境与海马神经元中多个基因启动子的表观遗传改变有关。
