Characterization of Differential Patterns of DNA Methylation Associated with Stress during Pregnancy: Determining Epigenetic Markers of Fetal Stress & Resilience

• Main Author: Kocher, Kristen M
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2023
• Subjects: Bioinformatics; Genetics; Obstetrics
• ISBN: 9798368437330

A feature of perinatal stress is impaired fetal brain development, resulting in reduced quality of life and life-long cognitive, learning, and affective-behavioral consequences for survivors. Advanced pre- and postnatal MRI technologies can identify disruptions in typical brain growth and maturation, and key brain-specific metabolites, resulting from in utero stressors to the fetus. However, the mechanisms by which these prenatal stressors disrupt fetal brain development remain unclear, and outcomes vary even for similar stressors, suggesting the existence of factors providing resilience or susceptibility to stress. Therefore, the overarching aim of this dissertation was to define the unique underlying epigenomic signatures associated with perinatal stressors in newborns, such as congenital heart disease, placenta-based disorders, and maternal psychological distress resulting from the COVID-19 pandemic. In addition, cell-free fetal DNA was leveraged to explore the detection of prenatal epigenetic stressors as the fetus develops. Maternal blood, placenta biopsies, and neonatal buccal and blood samples were collected as part of a comprehensive longitudinal phenotypic study in the Washington DC Metro region. We designed and validated a novel and robust analysis pipeline in R to filter and normalize output data from methylation array data specifically for this application. Strikingly, it was found that there are unique and overlapping epigenomic signatures associated with a variety of perinatal stressors in newborns when compared to controls. Increased methylation among all cohorts is associated with a known perinatal stress marker, glucocorticoid receptor NR3C1. Also represented among the stress cohorts is differential DNA methylation of the genes related to biological processes that involve neurodevelopment and stress response pathways. Together, the research presented here suggests that changes to the DNA methylome of newborns are associated with different types of pregnancy-related stress that may be directly implicated in biologically relevant neurological and stress-associated pathways.