Epigenome-Wide Patterns of DNA Methylation in Radiation Exposure and Gene Expression Open Access
Kennedy, Elizabeth (Fall 2017)
Abstract
DNA methylation is the most fundamental example of an epigenetic modification and is an integral epigenetic mechanism in humans. Through pathways that are not fully elucidated, DNA methylation can modulate gene transcription, and its patterns change readily over time in response to environmental or stochastic factors. For example, nearly identical methylation patterns among twins diverge over time, in a process known as epigenetic drift. Two natural questions that arise from this information are: how do DNA methylation patterns change in response to environment, and what are the downstream effects of those changes? Through my dissertation work, I have attempted to address both of these questions. First, I present a thorough review of extant literature in the epigenomics of radiation exposure. Second, I present a study that addresses acute and long-term changes to genome-wide CpG methylation patterns that occur following irradiation with varying qualities and quantities of radiation. We found that iron-ion, silicon-ion and X-ray irradiation induced rapid and stable changes in DNA methylation at distinct subsets of CpG sites. Importantly, we found that iron-irradiation-associated CpG sites could differentiate tumor and normal tissues for two human lung cancers. This study suggests that environmental exposures, like radiation, leave a lasting epigenetic imprint, and that these sites may be relevant to the development of complex diseases. Lastly, I present work that aimed to characterize and explore how DNA methylation patterns interact with gene expression, throughout the genome. Among CpGs at which methylation significantly associated with transcription (eCpGs), <50% fell within the canonical promoter region of the associated gene. Rather, we found that eCpGs were more common within enhancer and insulator elements and non-coding RNAs. We suggest that most changes in DNA methylation correlate negatively with transcription, and contrast our findings with the research that established opposing conventional wisdom. My dissertation work sheds new light on the interplay of the epigenome with the environment and with gene expression. Further, this work provides vital and biologically- relevant context for the interpretation of many existing and future studies of DNA methylation.
Table of Contents
Chapter I. Introduction 1
DNA methylation is the cornerstone of epigenetics 1
DNA methylation is a dynamic mark in the genome 3
Functional role of DNA methylation in the genome 5
DNA-methylation-based association studies 13
DNA methylation and gene expression 17
Genome-wide studies of DNA methylation provide insight
into its environmental response and regulatory potential 18
References 19
Chapter II. Epigenetic Memory of Space Radiation Exposure 31
DNA methylation 33
Effects of radiation on DNA methylation 34
Outstanding questions 35
Future perspectives 36
References 40
Chapter III. Galactic Cosmic Radiation Induces Stable Epigenome 45
Alterations Relevant to Human Lung Cancer
Introduction 46
Materials and methods 49
Results 54
Discussion 61
References 77
Chapter IV. An Integrated -Omics Analysis of the Epigenetic 84
Landscape of Gene Expression in Human Blood Cells
Introduction 85
Materials and methods 86
Results 94
Discussion 102
Conclusions 106
Supplemental Methods 129
References 135
Chapter V. Discussion 142
Common challenges emerge from different epigenetic studies 142
Overcoming statistical confounding 143
Combining –omics for improved interpretation 144
Combining bench and population science 146
Conclusion 148
References 149
About this Dissertation
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