Epigenomic dysregulation associated with intrauterine growth restriction and normal aging
Thompson, Reid F.
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Complex age-related diseases, such as type 2 diabetes mellitus (T2DM) and cardiovascular disease, result from an intricate interplay between environmental influences and multiple genetic pathways. Perturbations of the intrauterine environment can affect fetal development during critical periods of plasticity, and can increase susceptibility to these diseases decades later in life. Depending upon the postnatal environment, individuals can also acquire age-related diseases over the span of a lifetime. The exact mechanisms that mediate biological memory and the long-term effects of transient environmental exposures, particularly those that occur in utero, remain unclear. Preliminary evidence suggests that epigenetic dysregulation could play a critical role in this process. However, the patterns and extent of epigenetic changes associated with environment and age-related diseases have not been well characterized. I hypothesized that genome-wide analysis of epigenetic profiles would help to elucidate the complex relationship between the fetal and postnatal environments and the development of age-related disease..;These studies initially focus on the development, design, and validation of a custom epigenomic discovery platform, targeting DNA cytosine methylation specifically (Chapters 2--4). Subsequently, these exploratory tools are applied to the study of changing patterns of cytosine methylation in response to either the intrauterine or postnatal environments in both humans and animal models (Chapters 5--7). As such, they may help to explain the fetally-induced and postnatally acquired origins of age-related diseases. The overall findings of these studies are three-fold: (1) rat pancreatic islets show robust changes in DNA methylation at a suite of genes implicating dysregulation of islet vascularization and beta-cell development; (2) human cord blood-derived hematopoietic stem cells exhibit changes in DNA methylation at a number of sites including a well-characterized diabetes candidate gene; and (3) normal aging in rats causes tissue-specific epigenetic dysregulation. While the exact biological implications and mechanisms of these findings remain unclear, these changes reveal exciting patterns of epigenomic dysregulation that may mediate or degrade cellular memory processes to cause age-associated disease phenotypes.
- Theses and Dissertations