Epigenome-Wide Patterns of DNA Methylation in Radiation Exposure and Gene Expression Open Access

Kennedy, Elizabeth (Fall 2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/rv042t05q?locale=en
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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

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                 18

 

                             insight into its environmental response and regulatory

 

                             potential

 

                             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           142

 

                             studies     

 

                             Overcoming statistical confounding                                                143

 

                             Combining –omics for improved interpretation                      144

 

                             Combining bench and population science                               146

 

                             Conclusion                                                                               148

                             References                                                                               149

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