Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
University of Exeter Medical School, Exeter University, Exeter, UK.
Transl Psychiatry. 2014 Sep 2;4(9):e434. doi: 10.1038/tp.2014.80.
Epigenetic processes such as DNA methylation have been implicated in the pathophysiology of neurodevelopmental disorders including schizophrenia and autism. Epigenetic changes can be induced by environmental exposures such as inflammation. Here we tested the hypothesis that prenatal inflammation, a recognized risk factor for schizophrenia and related neurodevelopmental conditions, alters DNA methylation in key brain regions linked to schizophrenia, namely the dopamine rich striatum and endocrine regulatory centre, the hypothalamus. DNA methylation across highly repetitive elements (long interspersed element 1 (LINE1) and intracisternal A-particles (IAPs)) were used to proxy global DNA methylation. We also investigated the Mecp2 gene because it regulates transcription of LINE1 and has a known association with neurodevelopmental disorders. Brain tissue was harvested from 6 week old offspring of mice exposed to the viral analog PolyI:C or saline on gestation day 9. We used Sequenom EpiTYPER assay to quantitatively analyze differences in DNA methylation at IAPs, LINE1 elements and the promoter region of Mecp2. In the hypothalamus, prenatal exposure to PolyI:C caused significant global DNA hypomethylation (t=2.44, P=0.019, PolyI:C mean 69.67%, saline mean 70.19%), especially in females, and significant hypomethylation of the promoter region of Mecp2, (t=3.32, P=0.002; PolyI:C mean 26.57%, saline mean 34.63%). IAP methylation was unaltered. DNA methylation in the striatum was not significantly altered. This study provides the first experimental evidence that exposure to inflammation during prenatal life is associated with epigenetic changes, including Mecp2 promoter hypomethylation. This suggests that environmental and genetic risk factors associated with neurodevelopmental disorders may act upon similar pathways. This is important because epigenetic changes are potentially modifiable and their investigation may open new avenues for treatment.
表观遗传过程,如 DNA 甲基化,与神经发育障碍(包括精神分裂症和自闭症)的病理生理学有关。表观遗传变化可以由炎症等环境暴露引起。在这里,我们检验了这样一个假设,即产前炎症是精神分裂症和相关神经发育疾病的一个公认风险因素,它会改变与精神分裂症相关的关键大脑区域的 DNA 甲基化,即富含多巴胺的纹状体和内分泌调节中枢——下丘脑。高度重复元件(长散布元件 1(LINE1)和内粒 A 粒子(IAPs))上的 DNA 甲基化被用来代表全基因组 DNA 甲基化。我们还研究了 Mecp2 基因,因为它调节 LINE1 的转录,并且与神经发育障碍有已知的关联。我们从怀孕第 9 天接受病毒类似物 PolyI:C 或生理盐水处理的小鼠的 6 周龄后代中采集脑组织。我们使用 Sequenom EpiTYPER 测定法来定量分析 IAP、LINE1 元件和 Mecp2 启动子区域的 DNA 甲基化差异。在下丘脑,产前暴露于 PolyI:C 导致全基因组 DNA 明显低甲基化(t=2.44,P=0.019,PolyI:C 平均值为 69.67%,生理盐水平均值为 70.19%),特别是在雌性中,并且 Mecp2 启动子区域的甲基化明显降低(t=3.32,P=0.002;PolyI:C 平均值为 26.57%,生理盐水平均值为 34.63%)。IAP 甲基化没有改变。纹状体中的 DNA 甲基化没有明显改变。这项研究提供了第一个实验证据,表明生命早期暴露于炎症与表观遗传变化有关,包括 Mecp2 启动子低甲基化。这表明与神经发育障碍相关的环境和遗传风险因素可能作用于相似的途径。这很重要,因为表观遗传变化是潜在可改变的,对其的研究可能为治疗开辟新途径。