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- Creators: Department of Psychology
- Creators: Katsanos, Christos
Alzheimer’s Disease (AD) is the most prevalent form of dementia and is the sixth leading cause of death in the elderly. Evidence suggests that forms of stress, including prenatal maternal stress (PMS), could exacerbate AD development. To better understand the mechanism linking PMS and AD, we investigated behavior and specific epigenetic markers of the 3xTg-AD mouse model compared to aged-controls in offspring of stressed mothers and non-stressed mothers.
Chronic pain, or reoccurring pain lasting longer than three months, is frequently co- morbid with other chronic conditions. Physiological health problems such as overall general health, immune function, inflammation, stress, and sleep, as well as psychological problems like depression and anxiety are all associated with chronic pain. Previous studies have also shown evidence for the heritability of chronic pain, indicating a genetic factor for chronic pain in children. However, few studies have investigated potential epigenetic processes involved in childhood chronic pain. DNA methylation and other epigenetic processes are highly susceptible to changes during crucial developmental periods in children, and they are heavily influenced by psychosocial factors and environmental factors. During an immune response, various cytokines such as TNFα, IL-6, and CRP are released. Cytokines are involved in the production of pain through their pro-inflammatory properties. Additionally, there is evidence to believe they increase pain sensitivity acutely by acting directly on nociceptors. Previous studies have shown that higher levels of inflammatory cytokines are associated with more pain because the inflammatory response from our immune cells activates pain pathways. A constant or prolonged activation of the immune response may consequently result in chronic pain. In many cases of chronic pain, there is an increase in the circulating pro-inflammatory cytokines in the blood that also leads to hypersensitivity.
For my thesis, I conducted a study on a healthy pediatric cohort to investigate how DNA methylation of genes related to myelin may predict total white matter volume in a healthy pediatric cohort. The relatively new field of neuroimaging epigenetics investigates how methylation of genes in peripheral tissue samples is related to certain structural or functional features of the brain, as measured by neuroimaging data. Research has already demonstrated that methylation of genes in peripheral tissues is related to a variety of brain disorders. We hypothesized that methylation of myelin-related genes as measured in saliva samples would predict total white matter volume in a healthy pediatric cohort. After processing DNA methylation data from saliva samples from participants, multiple linear regressions were ran to determine if DNA methylation of myelin related genes was related to total white matter volume, as measured by data from structural MRIs. Results showed that these genes, which included MOG, MBP, and MYRF, significantly predicted total white matter volume. Two genes that were significant in our results have been previously shown to produce proteins that are essential to the structure of myelin.
Assessment of DNA methylation was performed on human skeletal muscle and blood using reduced representation bisulfite sequencing (RRBS) for high-throughput identification and pyrosequencing for site-specific confirmation. Sorbin and SH3 homology domain 3 (SORBS3) was identified in skeletal muscle to be increased in methylation (+5.0 to +24.4 %) in the promoter and 5’untranslated region (UTR) in the obese participants (n= 10) compared to lean (n=12), and this finding corresponded with a decrease in gene expression (fold change: -1.9, P=0.0001). Furthermore, SORBS3 was demonstrated in a separate cohort of morbidly obese participants (n=7) undergoing weight-loss induced by surgery, to decrease in methylation (-5.6 to -24.2%) and increase in gene expression (fold change: +1.7; P=0.05) post-surgery. Moreover, SORBS3 promoter methylation was demonstrated in vitro to inhibit transcriptional activity (P=0.000003). The methylation and transcriptional changes for SORBS3 were significantly (P≤0.05) correlated with obesity measures and fasting insulin levels. SORBS3 was not identified in the blood methylation analysis of lean (n=10) and obese (n=10) participants suggesting that it is a muscle specific marker. However, solute carrier family 19 member 1 (SLC19A1) was identified in blood and skeletal muscle to have decreased 5’UTR methylation in obese participants, and this was significantly (P≤0.05) predicted by insulin sensitivity.
These findings suggest SLC19A1 as a potential blood-based biomarker for obese, insulin resistant states. The collective findings of SORBS3 DNA methylation and gene expression present an exciting novel target in skeletal muscle for further understanding obesity and its underlying insulin resistance. Moreover, the dynamic changes to SORBS3 in response to metabolic improvements and weight-loss induced by surgery.
