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

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




                             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




                             Overcoming statistical confounding                                                143


                             Combining –omics for improved interpretation                      144


                             Combining bench and population science                               146


                             Conclusion                                                                               148

                             References                                                                               149

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