Intra-individual methylomics detects the impact of early-life adversity

Genetic and environmental factors interact during sensitive periods early in life to influence mental health and disease via epigenetic processes such as DNA methylation. However, it is not known if DNA methylation changes outside the brain provide an 'epigenetic signature' of early-life experiences. Here, we employed a novel intra-individual approach by testing DNA methylation from buccal cells of individual rats before and immediately after exposure to one week of typical or adverse life experience. We find that whereas inter-individual changes in DNA methylation reflect the effect of age, DNA methylation changes within paired DNA samples from the same individual reflect the impact of diverse neonatal experiences. Genes coding for critical cellular–metabolic enzymes, ion channels and receptors were more methylated in pups exposed to the adverse environment, predictive of their repression. In contrast, the adverse experience was associated with less methylation on genes involved in pathways of death and inflammation as well as cell-fate related transcription factors, indicating their potential upregulation. Thus, intra-individual methylome signatures indicate large-scale transcription-driven alterations of cellular fate, growth and function.遗传与环境因素在生命早期的敏感窗口期内相互作用，通过DNA甲基化（DNA methylation）等表观遗传过程（epigenetic processes）影响心理健康与疾病发生。然而目前尚不清楚，大脑以外区域的DNA甲基化变化是否能反映早期生命经历的“表观遗传特征”。本研究采用一种全新的个体内研究方法，对幼年大鼠在暴露于为期一周的正常或不良生活经历前后的颊黏膜细胞（buccal cells）DNA甲基化水平进行检测。研究结果显示，个体间的DNA甲基化变化主要反映年龄的影响，而同一受试者的配对DNA样本间的甲基化变化则体现了不同新生期经历的作用。暴露于不良环境的幼鼠，其编码关键细胞代谢酶、离子通道与受体的基因呈现更高的甲基化水平，这预示着这些基因的表达会受到抑制。与之相反，不良经历与参与细胞死亡、炎症通路以及细胞命运相关转录因子（transcription factors）的基因低甲基化相关，这提示这些基因可能出现表达上调。综上，个体内甲基化组（methylome）特征能够反映细胞命运、生长与功能的大规模转录调控改变。