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

灵长类动物压力和发育模型中的早期逆境和 DNA 甲基化。

• 批准号: 9310667
• 负责人: Jenny Tung
• 金额: $ 44.53万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310667
• 关键词: Address; Affect; Alcohol consumption; Aleurites; Animal Model; Animals; Attenuated; Behavior; Behavioral; Biological; Biological Assay; Blood; Cell division; Characteristics; Childhood; Complex; Coupled; DNA Methylation; Data; Development; Diet; Disease; Disease susceptibility; Ecosystem; Elderly; Environment; Epigenetic Process; Exposure to; Family; Fertility; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Variation; Genomic approach; Genomics; Genotype; Goals; Health; Health behavior; Human; Human Development; Immucyst; Individual; Individual Differences; Intervention; Joints; Kenya; Lead; Life; Life Cycle Stages; Life Stress; Light; Link; Long-Term Effects; Longitudinal Studies; Measures; Mediating; Methylation; Modeling; Molecular; Mosaicism; Outcome; Papio; Pathway interactions; Pattern; Physiological; Physiology; Play; Population; Predictive Factor; Predisposition; Primates; Process; Property; Quantitative Trait Loci; Randomized; Reporter; Reporting; Risk; Risk Behaviors; Role; Sampling; Shapes; Silk; Smoking; Social Behavior; Source; Stress; Testing; Time; Work; early experience; effective intervention; epigenome; experience; experimental study; genetic variant; genome-wide; genome-wide analysis; health care availability; infancy; insight; inter-individual variation; methylation pattern; mortality; nonhuman primate; rate of change; resilience; response; social; stressor; time use; trait; transcriptome sequencing

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.

概括 婴儿期和儿童期的压力经历会扰乱正常发育过程，产生 对人类健康产生终生影响。这些经历是晚年疾病和死亡率的有力预测因素 风险，以及暴露于多种早期生活压力源可能会产生更有效的影响。这些观察 表明不良的早期经历在生物学上已融入人类生理学中。然而， 介导嵌入过程的分子机制尚不清楚，这挑战了我们的能力 预测易感个体并制定有效的干预策略。 拟议工作的目标是利用天然动物基因组学的新兴模型 人群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，并可以通过对基因调控的影响来影响下游性状。然而，我们仍然知道 很少有人提及它在调节早期生活压力源影响方面的重要性。具体来说，我们不明白 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存在的程度，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在于收集环境数据和 随着时间的推移，同一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。为此，本提案利用了 肯尼亚安博塞利生态系统中的野生狒狒是经过深入研究的灵长类动物种群 是长达 8 个连续代的纵向研究对象。在安博塞利，早期生活压力源 即使没有吸烟等健康风险行为，也会对生育和生存产生深远影响， 饮酒或不良饮食。我们建议研究这些早期生命的表观遗传后果 全基因组范围内的压力源。具体来说，我们将测试主要早期项目的独特和累积效应 生活压力因素对血液中 DNA 甲基化水平的影响，研究早期逆境之间的关系- 相关的差异甲基化和基因调控，并研究生理和行为 将早期逆境与晚年表观基因组联系起来的途径。我们还将测试该程度 使用纵向收集的重复样本，早期生命影响的特征随着时间的推移而持续存在 个人和家庭。最后，我们将研究基因型、行为模式或环境是否 条件影响变化率，并使用孟德尔随机化分析来剖析因果路径 将早期环境与表观遗传模式联系起来。总之，我们的结果将提供一个不同寻常的 早期逆境与表观基因组之间关系的全面窗口。他们将因此而脱落 对表观遗传学在调节发育过程中早期逆境的长期影响中的作用有了新的认识。