Regulation of the DNA methylome in models of alcohol use disorders

Alcohol use disorder (AUD) is a highly prevalent and pernicious substance use disorder that is characterized by widespread changes to gene expression that may drive maladaptive behavioral progression from binge alcohol use to dependence and withdrawal. The prefrontal cortex (PFC) in mice and superior frontal cortex (SFC) in humans undergo changes in gene expression and function after chronic alcohol and are known to drive late-stage AUD behaviors. Epigenetic regulatory mechanisms are mediating factors between environment and gene expression. Because DNA-level epigenetic regulation of CpG dinucleotides is known to contribute to gene expression and disease pathology, I hypothesized that chronic alcohol exposure alters the global DNA-level epigenetic landscape, leading to changes in expression of genes that contribute to alcohol pathologies. In the first chapter, I provide a comprehensive review of the literature pertaining to DNA modifications and their role in AUD. In the second chapter, I use a mouse model of alcohol intoxication, dependence, and withdrawal to identify the effects of chronic alcohol on DNA-level epigenetic regulatory systems in the PFC and report that expression of DNA-modifying genes is dynamically regulated by alcohol exposure and withdrawal, and this regulation leads to downstream changes in global DNA methylation and hydroxymethylation. These changes are cell type-specific and are influenced not only by time since alcohol exposure, but also by sex. In the third chapter, I analyzed a human methylation microarray dataset to describe alcohol- and sex-related differential methylation in the genome. From this analysis, I present differential methylation in genes of molecular pathways involved in known contributing factors to AUD, including neuroimmune pathways and neuronal signaling and function, and describe how these changes to DNA methylation may contribute to gene expression and AUD phenotype. In the fourth chapter, I describe how normally epigenetically silenced genomic repeats are derepressed and propose a mechanism for how they may contribute to AUD-related neuroinflammation. I conclude by submitting that DNA-level epigenetic regulation is a significant contributor to AUD pathology and suggest that DNA modifications may be a potential therapeutic target requiring continued research into its functional role in regulating alcohol behaviors through mediation between genome and environment