DOI

10.17077/etd.mthqnslt

Document Type

Dissertation

Date of Degree

Summer 2018

Access Restrictions

Access restricted until 08/31/2019

Degree Name

PhD (Doctor of Philosophy)

Degree In

Genetics

First Advisor

Potash, James B.

First Committee Member

Bassuk, Alexander

Second Committee Member

Weiner, Joshua

Third Committee Member

Michaelson, Jacob

Fourth Committee Member

Stevens, Hanna

Abstract

Stress contributes to the development of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), and an intermediary factor between stress and psychiatric disorders may be epigenetics. Studies have shown altered DNA methylation (DNAm) in animal models of and humans with stress exposure and in individuals with PTSD and MDD. The availability of genome-wide experimental platforms has given us new tools to investigate DNAm, and in this dissertation these techniques have been used to further our current understanding of the epigenetics of stress.

We performed a genome-wide investigation in mice exposed to chronic stress that exhibit depressive- and anxious-like behaviors, examining DNAm changes within the dentate gyrus, a sub-region of the hippocampus that contributes to the stress response. Using the Methyl-Seq method, an intergenic region of chromosome X was shown to be differentially methylated with chronic stress, and this finding replicated in two additional cohorts of mice. In postmortem brain tissue of humans with MDD, an increase in DNAm within this intergenic region was also found.

Animal models do not fully capture the complexity of stress and psychiatric disorders in humans, but comparable studies in humans are limited by the difficulty of obtaining brain tissues. Instead, these studies have used peripheral tissues to examine DNAm changes related to stress and psychiatric disorders. To address the usefulness of these peripheral tissues, we employed the Illumina 450K and EPIC arrays to establish a resource that compares DNAm of the brain to that of blood, buccal, and saliva tissues.

Glucocorticoids (GCs) play an essential role in the stress response, and their dysregulation is seen in individuals with MDD and PTSD. To determine the role of GCs in stress-mediated epigenetic changes, buccal samples were obtained before and after individuals were given GCs in the context of oral surgery, and DNAm was analyzed using the Illumina EPIC array. Five CpGs were altered following this exposure, to a genome-wide significant degree. Further analysis revealed FDR-significant CpG changes to be in genes involved in steroid hormone biosynthesis and in genes differentially expressed with GC exposure.

Collectively, these results exemplify the complexity of DNAm changes associated with the stress response and provide potential avenues for elucidating their impact on psychiatric disorders.

Keywords

DNA methylation, Epigenetics, Genome-wide, Glucocorticoids, Stress

Pages

xiii, 169 pages

Bibliography

Includes bibliographical references (pages 142-169).

Copyright

Copyright © 2018 Patricia Rose Braun

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