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

Petersen, Rachel, Denver CO

Investigators

Abstract

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.