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

灵长类动物模型中社会地位在整个生命周期中的表观遗传后果

• 批准号: 8768775
• 负责人: Susan C. Alberts
• 金额: $ 23.6万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768775
• 关键词: Adult; Affect; Animal Model; Attention; Behavioral; Biological; Birth; Blood; Blood specimen; Buffers; Cardiovascular Diseases; Cessation of life; Complement; Complex; Conceptions; Coupled; DNA Methylation; Data; Diet; Disease susceptibility; Epigenetic Process; Foundations; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glucocorticoids; Goals; Health; Health Services Accessibility; Human; Immune response; Individual; Inflammatory; Kenya; Life; Life Cycle Stages; Life Experience; Link; Longevity; Longitudinal Studies; Measures; Mediating; Modeling; Molecular; Papio; Pattern; Physiological; Physiology; Plastics; Population; Primates; Probability; Property; Relative (related person); Reliance; Reporting; Risk; Role; Sampling; Schedule; Signal Transduction; Site; Smoking; Social Conditions; Social Environment; Social isolation; Social status; Solid; Staging; System; Testing; Time; Translating; Variant; Work; base; bisulfite; cost; disorder risk; experience; genome-wide; human population study; immune function; interest; life history; male; mortality; nonhuman primate; public health relevance; response; social; trait; transcriptome sequencing

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.

描述（由申请人提供）：早年和成年时期的社会逆境都会对人类健康产生重大而持久的影响。早年社会地位低下和社会孤立与晚年免疫反应的变化和心血管疾病发病率升高有关，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——对死亡风险有明确的影响。因此，生命早期受社会条件影响的特征至少在某种程度上会重新适应后来的社会环境。然而，调节这些双重特性（长期稳定性与可塑性变化的潜力）的机制仍然知之甚少。特别是，我们不了解将生命历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。这项工作的目标是利用一个强大的动物模型来应对人类的社会逆境（非人类灵长类动物的优势等级），以研究早期生命和成年社会地位对 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，可能作为社会环境、生理和健康之间的重要联系。然而，虽然已经对少数基因座的这种关系进行了详细研究，但我们尚不了解其在全基因组范围内的重要性，也不了解 DNA 甲基化因社会环境而发生的变化在多大程度上取决于暴露的时间。深入研究的灵长类动物种群可以作为解决这些问题的重要模型，因为直接观察已知个体从受孕到死亡的整个过程，并且社会环境影响不会与其他健康预测因素（例如获得医疗保健、饮食或吸烟）相混淆。该应用程序利用这样一个种群，即经过充分研究的肯尼亚安博塞利狒狒种群，来评估社会逆境与 DNA 甲基化之间的关系在生命历程中是否以及如何变化。具体来说，我们建议调查生命早期和成年时期的社会地位对血液中全基因组 DNA 甲基化模式的影响。我们将研究与早期生活社会地位、成年社会地位或两者相关的 DNA 甲基化目标；如果两者都有，我们将进一步测试这些是否 效果独立作用。由于 DNA 甲基化水平的变化并不总是影响其他性状的变化，因此我们还将用在同一抽血期间获得的同一个体的基因表达水平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 甲基化模式对下游基因表达水平的影响程度。总之，我们的结果将不仅有助于确定社会地位是否影响 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与健康之间更广泛关系的可能性。