Gene Expression and Epigenetic Modifications in Stress Response Genes Associated with Teenage and Adult

Suicide is a preventable public health issue that accounts for over a million deaths worldwide and is associated with the interaction of several biological, environmental, and neurological factors. Repeatedly, a dysregulated hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated to play a fundamental role and associated with psychiatric disorders and suicide, yet the mechanisms underlying this dysregulation are not clear. Decreased expression of the glucocorticoid receptor (GR) which is highly expressed in the hippocampus and prefrontal cortex (PFC) and is susceptible to epigenetic modulation is a strong indicator of HPA-axis hyperactivity. Additionally, epigenetic mechanisms have been shown to mediate environment x gene interaction through susceptible genes resulting in long-term changes to the genome. One of the most studied epigenetic mark, DNA methylation (DNAm) has been demonstrated to play a major role in various diseases including suicide. The main goal of this thesis was to test the hypothesis that HPA-axis coupled genes are dysregulated in specific areas of the limbic system and that epigenetic reprogramming, in the form of DNAm, maybe a key underlying factor mediating impaired GR signaling. Since there are distinct neurodevelopmental changes occurring during adolescence that may change the endophenotypes of suicide, teenage suicide-completers were studied separately from adult suicide-completers. In teenage suicide-completers, a focused approach was used to identify HPA-axis coupled genes that are differentially expressed and determine significant methylation changes at specific loci of candidate genes. To investigate steady-state DNAm levels, we analyzed DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and growth arrest- and DNA-damage-inducible proteins (GADD45) in both PFC and hippocampus. In adult suicide-completers, a hypothesis-free, genome-wide approach was taken to determine DNAm changes specific to neurons in the PFC. Initial bioinformatics reveals novel molecular pathways and networks where epigenetic regulation may be playing a key underlying factor. Together, these findings enhance our understanding of the complex transcriptional regulation of GR gene and also identify key regulators involved in HPA-axis dysregulation. Integrating DNAm and gene expression analysis provides valuable insight into molecular changes and help develop our current knowledge of how epigenetics contributes to alterations in molecular pathways involved in the pathophysiology of suicide.