Genome-wide Epigenetic Regulation by Early-Life Trauma
Genome-wide Epigenetic Regulation by Early-Life Trauma
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DOI：
10.1001/archgenpsychiatry.2011.2287
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发表时间：
2012-07-01
影响因子：
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通讯作者：
Turecki, Gustavo
中科院分区：
文献类型：
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作者：
Labonte, Benoit;Suderman, Matt;Turecki, Gustavo
我们的基因组适应环境的影响，部分是通过表观遗传机制，包括DNA甲基化。早期环境质量的变化与啮齿类动物DNA甲基化的改变有关，最近的数据表明人类对早期生活逆境的反应也有类似的过程。目的：确定早期生活创伤诱导的全基因组DNA甲基化改变。设计：儿童期严重虐待个体启动子甲基化的全基因组研究。患者、设置和主要结果测量：启动子DNA甲基化水平进行了分析，使用甲基化DNA免疫沉淀，然后在海马组织中的微阵列杂交从41名法裔加拿大男子（25名有严重的儿童虐待史和16名对照组）。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组分验证了组间甲基化差异。位点特异性启动子甲基化的功能后果进行了评估荧光素酶assays.Results：我们确定了362个差异甲基化的启动子与对照组相比，滥用的历史在个人。在这些启动子中，248个表现出高甲基化，114个表现出低甲基化。在5个最高甲基化的基因启动子中的DNA甲基化的验证和位点特异性定量表明，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最显着的差异甲基化，其中，Alsin（ALS 2）是最显着的发现。甲基化的ALS 2结构模拟的甲基化状态的样本中滥用自杀完成者表现出降低启动子转录活性与海马表达降低ALS 2 variants.Conclusion：童年逆境与海马神经元中的几个基因的启动子的表观遗传学改变。
Context: 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.Objective: To determine genome-wide DNA methylation alterations induced by early-life trauma.Design: 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.Results: 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.Conclusion: Childhood adversity is associated with epigenetic alterations in the promoters of several genes in hippocampal neurons.