Early life stress in humans (i.e. maltreatment, violence exposure, loss of a loved one) and in rodents (i.e. disrupted attachment or nesting, electric shock, restraint, predator odor) occurs during critical steps of neural circuit formation. ELS in humans is associated with increased risk for developmental psychopathology, including anxious and depressive phenotypes. The biological mechanisms underlying these potentially persistent maladaptive changes involve long-term epigenetic modifications, which have been suggested to be potentially transmissible to subsequent generations. DNA methylation is an epigenetic mechanism that modifies gene expression patterns in response to environmental challenges and influences mutation rates. It remains to be seen whether a functionally relevant fraction of DNA methylation marks can escape genome-wide erasures that occur in primordial germ cells and after fertilization within the zygote. Early life-stress-triggered changes in epigenetic mediated transmission of acquired behavioral traits among humans have been assessed mainly by targeting genes involved in the hypothalamic-pituitary-adrenal (HPA) axis, such as NR3C1 and FKBP5. Recently, researchers examining epigenetic transmission have begun to apply genome-wide approaches. In humans, reduced representation bisulfite sequencing (RRBS) was performed on peripheral samples that were obtained from individuals who were prenatally exposed to the “Dutch Hunger Winter”, resulting in two Differentially Methylated Regions (DMRs) in INSR and CPTIA genes that were functionally, biologically and technically validated, and significantly associated with birth weights and LDL cholesterol levels in offspring. In rodents, non-genomic intergenerational transmission of anxiety which was associated with differentially methylated enhancers that were putatively involved in lipid signaling and synaptic/neurotransmission in hippocampal granule cells, was discovered also using RRBS. Finally, transgenerational transmission of altered behaviors was associated with sperm-derived microRNAs produced by ELS male mice. The field of epigenetic transmission is just beginning to enter the epigenomic era by using genome-wide analyses. Such approaches remain of strong interest to human studies, first in order to help to assess the relevance of the previous targeted studies, and second to discover new important epigenetic modifications of potential clinical importance. New discoveries may help to assess how transmittable the negative impact of stress may be to offspring. The latter may open doors for future treatments and resilience-promoting interventions, as well as new approaches to treat the effects of childhood trauma before the onset of psychiatric disorder.

中文翻译：

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与早期生活压力相关的 DNA 甲基化特征的代际传递

人类（即虐待、暴力暴露、失去亲人）和啮齿动物（即依恋或筑巢中断、电击、束缚、捕食者气味）的早期生活压力发生在神经回路形成的关键步骤中。人类的 ELS 与发展性精神病理学风险增加相关，包括焦虑和抑郁表型。这些潜在持久的适应不良变化背后的生物学机制涉及长期的表观遗传修饰，这被认为可能会遗传给后代。DNA 甲基化是一种表观遗传机制，它会改变基因表达模式以应对环境挑战并影响突变率。DNA甲基化标记的功能相关部分是否能够逃脱在原始生殖细胞中和受精卵内受精后发生的全基因组删除仍有待观察。早期生活压力引发的表观遗传介导的人类后天行为特征传递的变化主要通过针对参与下丘脑-垂体-肾上腺（HPA）轴的基因（例如 NR3C1 和 FKBP5）进行评估。最近，研究表观遗传传递的研究人员已经开始应用全基因组方法。在人类中，对从产前暴露于“荷兰饥饿冬天”的个体获得的外周样本进行了还原代表性亚硫酸氢盐测序（RRBS），导致 INSR 和 CPTIA 基因中存在两个功能上的差异甲基化区域（DMR），经过生物学和技术验证，与后代的出生体重和低密度脂蛋白胆固醇水平显着相关。在啮齿类动物中，使用 RRBS 也发现了焦虑的非基因组代际传递，该传递与差异甲基化增强子相关，这些增强子可能参与海马颗粒细胞中的脂质信号传导和突触/神经传递。最后，行为改变的跨代传递与 ELS 雄性小鼠产生的精子来源的 microRNA 相关。通过使用全基因组分析，表观遗传传播领域刚刚开始进入表观基因组时代。这些方法仍然引起人类研究的浓厚兴趣，首先是为了帮助评估之前的目标研究的相关性，其次是为了发现具有潜在临床重要性的新的重要表观遗传修饰。新发现可能有助于评估压力的负面影响对后代的传播程度。后者可能为未来的治疗和恢复力促进干预措施以及在精神疾病发作之前治疗儿童创伤影响的新方法打开大门。