Longitudinal DNA methylation in a non-human primate model of early-life stress

项目摘要。应激相关精神障碍研究中的一个关键问题是关于应激相关精神障碍患者的时间相关性。 应激暴露的长期生物记忆的序列和分子机制。特别是， 这些分子变化转化为与精神疾病相关的功能性后果， 仍然难以捉摸先前的证据表明表观遗传修饰在应对压力暴露中的作用 即使跨越几代人;然而，许多问题仍然存在。我们建议利用生物样本 作为已经资助的非人灵长类动物（NHP）模型纵向发育研究的一部分收集 早期生活压力（ELS），以检查虐待诱导的全基因组的时间和动力学 从出生到青春期的DNA甲基化（DNAm）修饰。动态的表观遗传变化将是 与相关功能结果相关，包括与压力相关的神经内分泌、行为和 神经发育表型此外，该研究采用了交叉培养实验设计， 在出生时随机分组，将使我们能够回答有争议的问题， NHP中的虐待可能导致后代的表观遗传修饰，从而影响压力- 和后代中的创伤相关表型，即使他们自己没有直接暴露于创伤。我们的目标 目的是研究NHP中响应ELS的DNAm模式的形成和功能， 压力引起的DNA m跨代变化的影响。我们的中心假设是：1）ELS导致 年龄和严重程度依赖性DNA m变化，可预测神经内分泌、神经发育 和行为的改变，2）ELS在父母代将诱导DNAm的变化，在应激相关的 基因在下一代暗示生物遗传环境触发的表观遗传 这一点得到了我们初步数据的支持。我们将通过两个具体的实验来验证这两个假设。 目的：1）确定和比较DNAm概况，以及相应的功能结果，纵向从 暴露于ELS的NHP和匹配对照组的出生至青春期。2)利用独特的 交叉培养实验设计，我们将使用祖先虐待的信息来调查 祖先和当前虐待对后代DNA图谱的相互作用，以确定表观遗传和 几代人之间虐待婴儿的功能结果。我们的建议的重要性在于， 这些关于ELS的纵向对照研究和对ELS的代际表观遗传效应的调查， 人类的创伤暴露是不可行的。我们的NHP模型提供了一种直接的翻译方法， 将表观遗传特征与跨代功能读数相关联的独特可能性。的 该R21应用中的探索性研究将为未来作为R 01一部分的研究奠定基础 机制，将调查1）基因的分子功能，是表观遗传修饰的ELS在 NHPs和2）应激暴露的代际表观遗传效应的分子机制。

Project Summary. A key question in the study of stress-related psychiatric disorders concerns the temporal sequences and molecular mechanisms of long-term biological memories of stress exposure. In particular, which molecular changes translate into functional consequences relevant to psychiatric disorders often remains elusive. Prior evidence suggests a role for epigenetic modifications in response to stress exposure even across generations; however, many questions remain. We propose to leverage biological samples collected as part of an already funded longitudinal, developmental study in a non-human primate (NHP) model of early life stress (ELS) to examine the chronology and dynamics of maltreatment induced genome-wide modification of DNA methylation (DNAm) from birth to adolescence. The dynamic epigenetic changes will be correlated with relevant functional outcomes including stress-related neuroendocrine, behavioral and neurodevelopmental phenotypes. In addition, the fact that the study uses a cross-fostering experimental design with random group assignment at birth will allow us to answer the controversial question of whether infant maltreatment in NHP can lead to epigenetic modifications in subsequent generations, thus influencing stress- and trauma-related phenotypes in the offspring even without their own direct exposure to the trauma. Our goal is to examine the formation and function of DNAm patterns in response to ELS in NHPs and to investigate the effect of stress-elicited DNAm changes across generations. Our central hypotheses are that 1) ELS leads to age- and severity-dependent DNAm changes that are predictive of neuroendocrinological, neurodevelopmental and behavioral alterations, and 2) ELS in the parental generation will induce DNAm changes in stress-related genes in the subsequent generation implicating a biological inheritance of environmentally triggered epigenetic marks, which is supported by our preliminary data. We will test these two hypotheses through two specific aims: 1) Determine and compare DNAm profiles, and corresponding functional outcomes, longitudinally from birth through adolescence in NHPs exposed to ELS and matched controls. 2) Taking advantage of the unique cross-fostering experimental design, we will use information on ancestral maltreatment to investigate the interaction of ancestral and current maltreatment on DNAm profiles in offspring to determine the epigenetic and functional outcomes of infant maltreatment across generations. Our proposal's significance lays in the fact that these longitudinal, controlled studies on ELS and the investigation of intergenerational epigenetic effects of trauma exposure in humans are not feasible. Our NHP model offers a direct translational approach with the unique possibility to associate the epigenetic profiles with functional readouts across generations. The exploratory studies in this R21 application will lay the foundation for future studies as part of an R01 mechanism that will investigate 1) the molecular function of genes that are epigenetically modified by ELS in NHPs and 2) the molecular mechanism of intergenerational epigenetic effects of stress exposure.