CUIDA - Centro de Investigación del Abuso y la Adversidad Temprana, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins 340, Santiago, Chile.
Instituto de Ingeniería Biológica y Médica, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago, Chile.
J Dev Orig Health Dis. 2021 Oct;12(5):768-779. doi: 10.1017/S2040174420001075. Epub 2020 Dec 14.
Adverse childhood experiences (ACEs) are associated with a high risk of developing chronic diseases and decreased life expectancy, but no ACE epigenetic biomarkers have been identified until now. The latter may result from the interaction of multiple factors such as age, sex, degree of adversity, and lack of transcriptional effects of DNA methylation changes. We hypothesize that DNA methylation changes are related to childhood adversity levels and current age, and these markers evolve as aging proceeds. Two Gene Expression Omnibus datasets, regarding ACE, were selected (GSE72680 and GSE70603), considering raw- and meta-data availability, including validated ACE index (Childhood Trauma Questionnaire (CTQ) score). For DNA methylation, analyzed probes were restricted to those laying within promoters and first exons, and samples were grouped by CTQ scores terciles, to compare highly (ACE) with non-abused (control) cases. Comparison of control and ACE methylome profile did not retrieve differentially methylated CpG sites (DMCs) after correcting by false discovery rate < 0.05, and this was also observed when samples were separated by sex. In contrast, grouping by decade age ranges (i.e., the 20s, 30s, 40s, and 50s) showed a progressive increase in the number of DMCs and the intensity of changes, mainly related with hypomethylation. Comparison with transcriptome data for ACE subjects in the 40s, and 50s showed a similar age-dependent effect. This study provides evidence that epigenetic markers of ACE are age-dependent, but not defined in the long term. These differences among early, middle, and late adulthood epigenomic profiles suggest a window for interventions aimed to prevent the detrimental effects of ACE.
不良的童年经历（ACEs）与患慢性病和预期寿命缩短的风险增加有关，但直到现在还没有发现 ACE 的表观遗传生物标志物。后者可能是由于多种因素的相互作用，如年龄、性别、逆境程度以及缺乏 DNA 甲基化变化的转录效应。我们假设 DNA 甲基化变化与儿童期逆境水平和当前年龄有关，这些标记随着年龄的增长而演变。考虑到原始数据和元数据的可用性，包括经过验证的 ACE 指数（儿童创伤问卷（CTQ）评分），我们选择了两个关于 ACE 的基因表达综合数据集（GSE72680 和 GSE70603）。对于 DNA 甲基化，分析的探针仅限于位于启动子和第一外显子内的探针，并根据 CTQ 评分三分位数将样本分组，以比较高度（ACE）与非虐待（对照）病例。在通过错误发现率 < 0.05 校正后，比较对照和 ACE 甲基组谱并没有检索到差异甲基化 CpG 位点（DMC），当按性别分离样本时也观察到了这一点。相比之下，按十年年龄范围（即 20 多岁、30 多岁、40 多岁和 50 多岁）分组显示 DMC 的数量和变化强度逐渐增加，主要与低甲基化有关。与 ACE 受试者在 40 多岁和 50 多岁的转录组数据进行比较显示出类似的年龄依赖性效应。这项研究提供了证据，表明 ACE 的表观遗传标志物是年龄依赖性的，但不能长期确定。这些早期、中年和晚年的表观基因组谱之间的差异表明，有一个干预的窗口期，旨在预防 ACE 的不利影响。
