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


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

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
Subfield / Discipline
  • English
Research Field
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files