McGill Group for Suicide Studies, McGill University, Montreal, Quebec, Canada.
Biol Psychiatry. 2012 Jul 1;72(1):41-8. doi: 10.1016/j.biopsych.2012.01.034. Epub 2012 Mar 22.
Childhood abuse alters hypothalamic-pituitary-adrenal (HPA) function and increases the risk of suicide. Hippocampal glucocorticoid receptor (GR) activation regulates HPA activity, and human GR expression (hGR) is reduced in the hippocampus of suicide completers with a history of childhood abuse compared with controls. The abuse-related decrease in hGR expression associates with increased DNA methylation of the promoter of the hGR(1F) variant in the hippocampus.
In this study, we investigated the expression and methylation levels of other hGR splice variants in the hippocampus and anterior cingulate gyrus in suicide completers with and without a history of childhood abuse and in controls. Expression levels were quantified using quantitative reverse-transcriptase polymerase chain reaction and promoter methylation was assessed by pyrosequencing.
In the hippocampus, the expression of total hGR and variants 1(B), 1(C), and 1(H) was decreased in suicide completers with histories of abuse compared with suicides with no histories of abuse and with control subjects. In the anterior cingulate gyrus, however, no group differences in hGR total or variant expression were found. Site-specific methylation in hGR1(B) and 1(C) promoter sequences were negatively correlated with total hGR messenger RNA, as well as with hGR1(B) and 1(C) expression. Luciferase assay showed that methylation in hGR promoter decreases transcriptional activity. In contrast, total and site-specific methylation in the hGR1(H) promoter was positively correlated with total hGR messenger RNA and hGR1(H) expression.
These findings suggest that early-life events alter the expression of several hGR variants in the hippocampus of suicide completers through effects on promoter DNA methylation.
儿童期虐待会改变下丘脑-垂体-肾上腺（HPA）功能，并增加自杀的风险。海马糖皮质激素受体（GR）的激活调节 HPA 活性，与没有儿童期虐待史的对照组相比，有儿童期虐待史的自杀者的海马体中人类 GR 表达（hGR）减少。hGR 表达的这种与虐待相关的减少与 hGR(1F)变体启动子的 DNA 甲基化增加有关。
在这项研究中，我们研究了有和没有儿童期虐待史的自杀者的海马体和前扣带回中 hGR 剪接变体的表达和甲基化水平，并与对照组进行了比较。使用定量逆转录聚合酶链反应定量了表达水平，并用焦磷酸测序评估了启动子甲基化。
在海马体中，与没有虐待史的自杀者和对照组相比，有虐待史的自杀者的总 hGR 和变体 1(B)、1(C)和 1(H)的表达减少。然而，在前扣带回中，hGR 总表达或变体表达没有发现组间差异。hGR1(B)和 1(C)启动子序列的特定部位甲基化与总 hGR 信使 RNA 以及 hGR1(B)和 1(C)的表达呈负相关。荧光素酶测定表明 hGR 启动子的甲基化降低了转录活性。相比之下，hGR1(H)启动子的总甲基化和特定部位的甲基化与总 hGR 信使 RNA 和 hGR1(H)的表达呈正相关。
这些发现表明，早期生活事件通过影响启动子 DNA 甲基化，改变了自杀者海马体中几种 hGR 变体的表达。
