Postdoctoral Fellowship: SPRF: Early Life Adversity Effects on DNA Methylation: Developmental Trajectories and Functional Consequences

该奖项是美国国家科学基金会社会、行为和经济科学博士后研究奖学金（SPRF）计划的一部分。SPRF计划的目标是为学术界、工业界或私营部门和政府的科学事业准备有前途的早期职业博士级科学家。SPRF奖励包括在知名科学家的赞助下进行为期两年的培训，并鼓励博士后进行独立研究。美国国家科学基金会寻求促进科学界各阶层的科学家，包括那些未被充分代表的群体的科学家，参与其研究项目和活动；博士后阶段被认为是实现这一目标的一个重要的专业发展阶段。每个博士后必须解决各自学科领域的重要科学问题。在范德比尔特大学Amanda J. Lea博士的赞助下，这个博士后奖学金奖支持一位早期职业科学家调查早期生活逆境的影响。众所周知，早年经历的逆境对健康的影响会持续到成年，然而，将早年生活环境与晚年健康联系起来的生物学机制尚不清楚。DNA甲基化是一种影响基因调控和疾病的表观遗传过程，是一种潜在的机制，通过这种机制，早期生活经历可能会嵌入生物体的生理学中，从而影响以后的健康。这项研究提出了一项大规模的调查，即在非人类灵长类动物恒河猴中，早期生活逆境如何预测身体所有主要器官系统的DNA甲基化和基因调控。非人灵长类动物是了解人类生物学的一个很好的比较类群，因为我们有着悠久的共同进化历史，在生理和社会行为上有着相似之处。这项研究将是迄今为止对早期生活逆境如何影响非人类灵长类动物DNA甲基化的最全面的系统范围内的调查，这将有助于我们理解灵长类动物（包括人类）如何感知和应对社会生态挑战，以及这些经历如何产生行为和健康差异。在美国，三分之一的儿童在童年时期经历过不良事件，而逆境的经历是不成比例的。通过形成对童年逆境如何改变生理的更深入的了解，本研究旨在为未来医疗干预措施的发展奠定基础，改善受影响最严重社区个人的生活。在灵长类物种中，早期生活逆境（ELA）与成年后健康状况不佳以及进化适应度（如寿命、繁殖率和后代存活率）相关。该项目旨在更好地了解早期生活中经历的困难如何影响DNA甲基化（DNAm），这是一种表观遗传基因调控机制，涉及介导早期生活环境与成年表型之间的关系。虽然已知DNAm和ELA之间存在相关性，但尚未对ELA相关的DNAm模式进行全面的系统范围表征。此外，DNAm驱动或抑制基因表达（影响表型的必要前标）的程度是高度可变且知之甚少的。为了解决这些知识上的空白，该项目将利用293只自由放养的恒河猴的行为、人口统计学和基因组数据，并将研究ela相关dna在所有主要器官系统的10个不同组织中的存在和发育轨迹。此外，该项目将通过以下方法确定ela相关DNAm在3种组织（血液、肾脏和肺）中的功能重要性：1)评估染色质可及性和ela相关位点附近基因的表达；2)使用大规模平行报告基因分析实验测试位点特异性DNAm对基因表达的影响。这项研究将构成迄今为止在非人类灵长类动物中对ELA相关DNAm进行的最全面的系统范围内的调查，并将是第一个将基因位点特异性DNAm数据与体内基因调控测量和能够测试ELA背景下甲基化表达因果关系的实验分析相配对的研究。本文提出的创新方法将为表观遗传机制提供新的见解，使自然生活的灵长类动物能够感知和应对社会生态挑战，并将为社会生态环境如何“深入皮肤”影响与人类进化和健康相关的表型变异提供见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This award was provided as part of NSF's Social, Behavioral and Economic Sciences Postdoctoral Research Fellowships (SPRF) program. The goal of the SPRF program is to prepare promising, early career doctoral-level scientists for scientific careers in academia, industry or private sector, and government. SPRF awards involve two years of training under the sponsorship of established scientists and encourage Postdoctoral Fellows to perform independent research. NSF seeks to promote the participation of scientists from all segments of the scientific community, including those from underrepresented groups, in its research programs and activities; the postdoctoral period is considered to be an important level of professional development in attaining this goal. Each Postdoctoral Fellow must address important scientific questions that advance their respective disciplinary fields. Under the sponsorship of Dr. Amanda J. Lea at Vanderbilt University, this postdoctoral fellowship award supports an early career scientist investigating the effects of early life adversity. Adversity experienced in early life is known to have health consequences lasting into adulthood, however the biological mechanism connecting early life environment to later life health is unknown. DNA methylation, an epigenetic process that can impact gene regulation and disease, is one potential mechanism by which early life experiences may become embedded within an organism’s physiology to impact health later in life. This research proposes a large-scale investigation of how early life adversity predicts DNA methylation and gene regulation throughout all major organ systems of the body in a non-human primate, the rhesus macaque. Non-human primates are an excellent comparative taxa for understanding human biology due to our long shared evolutionary history and our similarities in physiology and social behavior. This study will be the most comprehensive systems-wide interrogation of how early life adversity impacts DNA methylation in a non-human primate to date, which will aid in our understanding of how primates (including humans) sense and respond to socio-ecological challenges and how behavioral and health disparities emerge from these experiences. One third of children in the US experience an adverse event during childhood, and adversity is disproportionately experienced. By forming a greater understanding of how childhood adversity alters physiology, this study aims to lay the groundwork for future development of medical interventions improving the lives of individuals from the most affected communities.Across primate species, early life adversity (ELA) is associated with poor adult health and proxies of evolutionary fitness, such as longevity, reproductive rate, and offspring survival. This project aims to better understand how hardship experienced during early life influences DNA methylation (DNAm), an epigenetic gene regulatory mechanism that has been implicated in mediating the relationship between early life environment and adult phenotype. Although there are known correlations between DNAm and ELA, there has yet to be a thorough systems-wide characterization of ELA-associated DNAm patterns. Moreover, the extent to which DNAm drives or suppresses gene expression, a necessary pre-cursor for impacting phenotype, is highly variable and poorly understood. To address these gaps in knowledge, this project will leverage behavioral, demographic, and genomic data from 293 free-ranging rhesus macaques and will investigate the presence and developmental trajectory of ELA-associated DNAm in 10 different tissues spanning all major organ systems. Furthermore, this project will determine the functional importance of ELA-associated DNAm in 3 tissues (blood, kidney, and lung) by 1) assessing chromatin accessibility and the expression of genes near ELA-associated sites, and 2) using massively parallel reporter assays to experimentally test the impact of locus-specific DNAm on gene expression. This study will constitute the most comprehensive systems-wide interrogation of ELA-associated DNAm in a non-human primate to date and will be the first to pair locus-specific DNAm data with both in vivo measurements of gene regulation and experimental assays capable of testing for causal methylation- expression relationships in the context of ELA. The innovative approaches proposed here will provide new insight into the epigenetic mechanisms that allow naturally living primates to sense and respond to socio-ecological challenges, and will provide insight into how the socio-ecological environment “gets under the skin” to influence phenotypic variation relevant to human evolution and health.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.