Epigenetic Consequences of Social Status across the Life Span in a Primate Model

描述（由申请人提供）：社会逆境，无论是在生命早期和成年，可以对人类健康产生重大和持久的影响。早期的社会地位低下和社会孤立与免疫反应的变化和晚年心血管疾病的发病率升高有关，即使地位差异被消除。与此同时，成年期的社会逆境--与任何早期生活经历无关--对死亡风险有着充分的影响。因此，在生命早期受到社会条件影响的特征至少在某种程度上对后来的社会环境有反应。然而，调节这些双重性质的机制长期稳定性加上可塑性的变化潜力仍然知之甚少。特别是，我们不了解将整个生命过程中的社会经验转化为影响健康和疾病风险的生理变化的分子机制。这项工作的目标是利用一个强大的动物模型来研究人类的社会逆境--非人类灵长类动物的优势地位--来调查早期生活和成年社会地位对DNA甲基化水平变化的相对贡献。DNA甲基化是一种表观遗传机制，可能是社会环境，生理和健康之间的重要联系。然而，虽然这种关系已经在少数位点上进行了详细的研究，但我们还不了解它在全基因组范围内的重要性，也不知道DNA甲基化在多大程度上取决于暴露的时间。深入研究灵长类种群可以作为这些问题的重要模型，因为已知的个体从受孕到死亡都是直接观察的，社会环境影响不会被其他健康预测因素（如获得医疗保健，饮食或吸烟）所混淆。该应用程序利用了这样一个群体，即经过充分研究的肯尼亚Amboseli狒狒群体，来评估社会逆境和DNA甲基化之间的关系是否以及如何在生命过程中发生变化。具体来说，我们建议调查社会地位的贡献，在生命早期和成年后，在血液中的全基因组DNA甲基化的模式。我们将研究与早期社会地位、成年社会地位或两者相关的DNA甲基化靶点;如果两者都有，我们将进一步测试这些靶点是否与早期社会地位、成年社会地位或两者相关。 效果是独立的。由于DNA甲基化水平的变化并不总是影响其他性状的变化，我们还将用同一个人在同一次抽血中获得的基因表达水平的数据来补充这些数据。基因表达数据将揭示对社会地位敏感的DNA甲基化模式也影响下游基因表达水平的程度。总之，我们的研究结果不仅有助于确定社会地位是否会影响DNA甲基化，还有助于确定生命不同阶段的作用。 这种关系的过程以及表观遗传机制解释社会逆境和健康之间更广泛关系的可能性。

DESCRIPTION (provided by applicant): Social adversity, both in early life and adulthood, can have major and long-lasting impacts on human health. Low social status and social isolation in early life have been linked to changes in the immune response and elevated rates of cardiovascular disease later in life, even when status differences are erased. At the same time, social adversity in adulthood - unconnected to any early life experience - has well-documented effects on mortality risk. Thus, traits that are influenced by social conditions early in life reman, at least to some degree, responsive to later social environments. However, the mechanisms that mediate these dual properties-long-term stability coupled with the potential for plasticity an change-remain poorly understood. In particular, we do not understand the molecular mechanisms that translate social experiences across the life course into physiological changes that affect health and disease risk. The goal of the proposed work is to leverage a powerful animal model for social adversity in humans-dominance rank in nonhuman primates-to investigate the relative contributions of early life and adult social status to variation in DNA methylation levels. DNA methylation is an epigenetic mechanism that may serve as an important link between social environment, physiology, and health. However, while this relationship has been investigated in detail for a handful of loci, we do not yet understand its importance genome-wide, or the degree to which changes in DNA methylation in response to the social environment depend on the timing of exposure. Intensively studied primate populations can serve as important models for these questions because known individuals are directly observed from conception to death, and social environmental effects are not confounded by other predictors of health, such as access to health care, diet, or smoking. This application takes advantage of one such population, the well-studied Amboseli baboon population of Kenya, to assess whether and how the relationship between social adversity and DNA methylation changes over the life course. Specifically, we propose to investigate the contribution of social status, in both early life and in adulthood, to patterns of genome-wide DNA methylation in blood. We will investigate targets of DNA methylation that are associated with early life social status, adult social status, or both; if both, we will further test whether these effects act independently. Because variation in DNA methylation levels does not always affect variation in other traits, we will also complement these data with data on gene expression levels from the same individuals, obtained during the same blood draw. The gene expression data will reveal the degree to which DNA methylation patterns that are sensitive to social status also influence downstream gene expression levels. Together, our results will help establish not only whether social status influences DNA methylation, but also the role of different stages of the life course in this relationship and the likelihood that epigenetic mechanisms explain broader relationships between social adversity and health.