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

总结 婴儿期和儿童期的压力经历会破坏正常发育的过程， 对人类健康的终身影响。这些经历是晚年疾病和死亡率的有力预测因素 风险和暴露于多种早期生活压力源可能会产生更强大的影响。这些观察结果 这表明早期不良经历在生物学上已深深植根于人类生理学中。但 介导包埋过程的分子机制还不清楚，挑战了我们的能力， 预测易感个体并制定有效的干预策略。 这项工作的目标是利用一个新兴的模型，在自然动物的基因组学 研究早期生活压力对全基因组DNA甲基化水平的影响。DNA 甲基化是一种表观遗传机制，受早期生活条件的强烈影响，可以保持稳定， 随着时间的推移，并可以通过其对基因调控的影响影响下游性状。但是我们仍然知道 很少有人知道它在调解早期生活压力因素的影响方面的重要性。具体来说，我们不理解 受早期生活压力影响最大的基因和途径，这些影响随时间持续的程度，或 介导个体间易感性差异的环境、行为或遗传因素。部分 回答这些问题的挑战之一在于收集环境数据的困难， 同一个人和家庭的生物样本。 动物模型为克服这一挑战提供了机会。为此，该提案利用了 肯尼亚安博塞利生态系统中的野生狒狒， 被纵向研究的对象多达8个连续的世代。在安博塞利，早期生活压力源 对生育和生存有着深远的影响，即使没有吸烟等健康风险行为， 饮酒或不良饮食。我们建议调查这些早期生命的表观遗传后果 在基因组范围内的压力源。具体来说，我们将测试早期重大疾病的独特和累积效应， 生活压力对血液中DNA甲基化水平的影响，研究早期逆境与 相关的差异甲基化和基因调控，并探讨生理和行为 连接早期逆境和后期表观基因组的途径。我们还将测试 早期生命影响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，我们将调查基因型、行为模式或环境因素是否影响了基因型、行为模式或环境因素。 条件影响变化率，并使用孟德尔随机化分析来剖析因果途径 将早期环境与表观遗传模式联系起来。我们的结果将共同提供不同寻常的 早期逆境和表观基因组之间关系的全面窗口。它们将因此而脱落 新的光到表观遗传学的作用，在调解长期影响的早期逆境在发展过程中。

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.