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，无论是在早期生活还是成年，都可能对人类健康产生重大和持久的影响。早年的低社会地位和社会孤立与晚年免疫反应的变化和心血管疾病发病率的上升有关，即使地位差异被抹去。与此同时，成年期的社会逆境--与任何早期生活经历无关--对死亡风险的影响是有据可查的。因此，在生命早期受到社会环境影响的特征，至少在某种程度上，会对后来的社会环境做出反应。然而，调节这些双重属性的机制--长期稳定性和可塑性的可能性--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历转化为影响健康和疾病风险的生理变化的分子机制。这项拟议工作的目标是利用一种强大的人类社会逆境动物模型--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纽带。然而，虽然已经对少数几个基因座的这种关系进行了详细的研究，但我们还不知道它在全基因组范围内的重要性，也不知道DNA甲基化变化在多大程度上取决于暴露的时间。深入研究的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所混淆，例如获得医疗保健、饮食或吸烟的机会。这个应用程序利用了一个这样的种群，肯尼亚经过充分研究的安博塞利狒狒种群，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。具体地说，我们建议调查社会地位对血液中全基因组DNA甲基化模式的贡献，无论是在早期生活还是在成年阶段。我们将调查与早期生活社会地位、成人社会地位或两者都相关的DNA甲基化目标；如果两者都有，我们将进一步测试这些 效果是独立起作用的。因为DNA甲基化水平的变化并不总是影响其他特征的变化，我们也将用来自相同个体的基因表达水平的数据来补充这些数据，这些数据是在相同的抽血过程中获得的。基因表达数据将揭示对社会地位敏感的DNA甲基化模式对下游基因表达水平的影响程度。总之，我们的结果不仅有助于确定社会地位是否影响DNA甲基化，而且还有助于确定生命不同阶段的作用 这种关系的进程，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.