Epigenetic underpinnings of pediatric immune system development

The first 1000 days of life, from conception to about 2 years of age, are a critical window of development establishing long term health trajectories. One mechanism through which exposures and experiences can translate into biological outcomes is through epigenetics, modifications that occur around the genome without altering the underlying sequence. These changes allow exposures to “get under the skin,” resulting in the biological embedding of exposures that can lead to lasting changes on phenotypic and developmental trajectories. DNA methylation (DNAm), one of many epigenetic modifications, is a well-studied and valuable source of information since the modification is both mitotically heritable and dynamically responsive to stimuli, exposures, stressors, and many other environmental influences. DNAm is also associated with changes in gene expression and cell type identity. As such, it is particularly useful for studying development, as it captures the evolving identities of cell types and the maturation of their functions over time. The overall aim of this dissertation was to characterize DNAm changes in pediatric populations with a focus on the immune system and health. First, I conducted epigenome wide association studies (EWAS) looking for associations between DNAm levels in immune genes and either time or sex. There were few significant differences during this time frame which was surprising given the rapid development that occurs during early life and the significant differences between males and females were largely consistent regardless of the time point. Next, using DNAm collected in infancy, I tested associations with the number of respiratory infections experienced later in life and found the presence of increased DNAm in two genes, both with immune functions, associated with increased incidence of illness. Lastly, I sought to integrate two ‘omics, DNAm and the microbiome, with the goal of understanding potential molecular underpinnings of these two important systems in human development and found both microbiome and DNAm signatures associated with cell type proportion, suggesting a role in normative immune system development. Collectively, these efforts contributed to a broader understanding of DNAm patterns and dynamics during early childhood development.