Indiana University-Purdue University Indianapolis (IUPUI) / The emerging field of epigenetics is expanding our understanding of how
biological diversity is generated in the face of genetic limitations. One epigenetic
mechanism in particular, DNA methylation, has demonstrated a dynamic range during
neural development. Here, we provide evidence that DNA methylation occurs as a cell
unique program aiding in the regulation of neurodevelopmental gene expression. DNA
methylation has demonstrated sensitivity to external inputs ranging from stress to
chemical exposure and dietary factors. To explore DNA methylation as a means of
communicating early-life stress to the brain, we utilized a mouse model of fetal alcohol
spectrum disorders (FASD). FASD presents a range of neurodevelopmental deficits and
is a leading cause of neurodevelopmental disabilities in the United States. Predicated on
the knowledge of alcohol's teratogenic role in brain development, we describe that the
normal pattern of cortical DNA methylation and epigenetic correlates is similarly
impacted by prenatal alcohol exposure. Due to the biochemical interaction of alcohol
metabolism and the pathways regulating DNA methylation synthesis, we further
investigated whether dietary manipulation could normalize the cortical DNA methylation
program and aid in the protection of FASD characteristics. We found that the alcohol
sensitive DNA methylation landscape is dually capable of registering dietary
intervention, demonstrating normalization of disease-related patterns in the cortex and improved neurodevelopmental gene expression and morphology. Finally, we investigated
the DNA methylation landscape in a crucial corticodevelopmental gene to more
accurately define the breadth and scope of the environmental impacts at the nucleotide
level. We found that alcohol and dietary supplementation are selective for regions
associated with transcriptional control. Collectively, the evidence supports that DNA
methylation plays a regulatory role in development and that its sensitivity to external
inputs is dynamic and detectable at the smallest genomic level. Importantly, DNA
methylation landscapes are adaptable and thus bear diagnostic and therapeutic potential.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/13854 |
| Date | 01 June 2017 |
| Creators | Resendiz, Marisol |
| Contributors | Zhou, Feng |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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