Early adversity and DNA methylation in a primate model of stress and development.

摘要 婴儿期和儿童期的紧张经历会扰乱正常的发育过程，产生 对人类健康的终生影响。这种经历是未来疾病和死亡率的有力预测因素。 风险，以及暴露在多种早期生活应激源中，可能会产生更大的影响。这些观察结果 这表明，不良的早期经历在生物学上植根于人类生理。然而， 调节嵌入过程的分子机制还不是很清楚，这挑战了我们的能力 预测易感人群并制定有效的干预策略。 这项拟议工作的目标是利用一种新兴的天然动物基因组学模型。 研究早期生活压力对全基因组DNA甲基化水平的影响。脱氧核糖核酸 甲基化是一种表观遗传机制，受早期生命条件的强烈影响，可以保持稳定 随着时间的推移，它可以通过对基因调控的影响来影响下游特征。然而，我们仍然知道 很少提到它在调节早期生活应激源的影响方面的重要性。具体地说，我们不理解 受早期生活压力影响最大的基因和途径，这些影响随着时间的推移持续的程度，或者 敏感度环境、行为或遗传因素导致个体间易感性差异的因素零件 回答这些问题的挑战之一在于收集环境数据和 随着时间的推移，相同的个人和家庭的生物样本。 动物模型提供了克服这一挑战的机会。要做到这一点，这项提议利用了 肯尼亚安博塞利生态系统中的一种经过深入研究的灵长类动物种群，它们拥有 成为连续8代人的纵向研究对象。在安博塞利，早年生活的压力源 对生育和生存有深远的影响，即使在没有吸烟等危害健康的行为的情况下， 饮酒，或者饮食不佳。我们建议研究这些早期生命的表观遗传学后果 全基因组范围内的压力源。具体地说，我们将测试重大早期事件的独特和累积效果 生活应激源对血液中DNA甲基化水平的影响，调查早期逆境- 相关的差异甲基化和基因调控，并研究生理和行为 连接早期逆境和晚年生活中的表观基因组的途径。我们还将测试在多大程度上 早期生命效应的特征随着时间的推移而持续存在，使用纵向收集的重复样本 个人和家庭。最后，我们将调查基因、行为模式或环境 条件会影响变化率，并使用孟德尔随机化分析来剖析原因路径 这将早期环境与表观遗传模式联系在一起。总之，我们的结果将提供一个不同寻常的 全面了解早期逆境和表观基因组之间的关系。他们将会因此而脱掉 对表观遗传学在调节早期逆境在发育过程中的长期影响的作用的新认识。

Summary Stressful experiences in infancy and childhood can disrupt the process of normal development, producing life-long impacts on human health. Such experiences are powerful predictors of later life disease and mortality risk, and exposure to multiple early life stressors can have even more potent effects. These observations suggest that adverse early experiences become biologically embedded in human physiology. However, the molecular mechanisms that mediate the embedding process are not well understood, challenging our ability to predict susceptible individuals and develop effective intervention strategies. The goal of the proposed work is to leverage an emerging model for genomics in natural animal populations to investigate the effects of early life stress on genome-wide DNA methylation levels. DNA methylation is an epigenetic mechanism that is strongly influenced by early life conditions, can remain stable over time, and can influence downstream traits through its effects on gene regulation. However, we still know little about its importance in mediating the effects of early life stressors. Specifically, we do not understand the genes and pathways most affected by early life stress, the degree to which these effects persist over time, or the environmental, behavioral, or genetic factors that mediate inter-individual differences in susceptibility. Part of the challenge in answering these questions lies in the difficulty of collecting environmental data and biological samples for the same individuals and families over time. Animal models provide an opportunity to overcome this challenge. To do so, this proposal takes advantage of an intensively studied primate population, the wild baboons of the Amboseli ecosystem of Kenya, that have been the subjects of longitudinal study for up to 8 contiguous generations. In Amboseli, early life stressors have profound effects on fertility and survival, even in the absence of health risk behaviors like smoking, alcohol consumption, or poor diet. We propose to investigate the epigenetic consequences of these early life stressors on a genome-wide scale. Specifically, we will test the unique and cumulative effects of major early life stressors on DNA methylation levels in blood, investigate the relationship between early adversity- associated differential methylation and gene regulation, and investigate the physiological and behavioral pathways that connect early adversity to the epigenome later in life. We will also test the degree to which the signature of early life effects persists over time, using longitudinally collected repeated samples from individuals and families. Finally, we will investigate whether genotype, behavioral patterns, or environmental conditions affect rates of change, and use Mendelian randomization analyses to dissect the causal pathways that link the early environment to epigenetic patterns. Together, our results will provide an unusually comprehensive window into the relationship between early adversity and the epigenome. They will thus shed new light into the role of epigenetics in mediating the long-term effects of early adversity during development.