Chronic Pain And Dna Methylation In The Mouse Prefrontal Cortex PDF Download

"Cancer and chronic pain are two common pathologies affecting millions of patients worldwide. Much like most other disease states, they can be determined genetically, environmentally, or both. Unlike the static genome, the epigenome is responsible for interpreting environmental interactions and is often altered in disease states. A subset of epigenetic modifications, known as DNA methylation, is capable of mediating gene silencing. In this thesis, two cases will be explored probing the nature of DNA methylation in cancer and in peripheral neuropathy. Aberrant DNA methylation is a common hallmark of cancer often resulting in the methylation of tumor suppressors and the demethylation of oncogenes. The identity of a DNA methylase, however, remains elusive. One candidate, methyl binding domain 2 (MBD2), has been previously characterized as a demethylase and also functions as a transcriptional repressor. One possible explanation for its role as a repressor may involve the direct activation of a repressor which can then mediate silencing. An attractive class of genes for this model are microRNAs, which are capable of binding several targets in the cell and mediate their silencing. We therefore test the hypothesis that MBD2 is capable of activating a microRNA which is capable of negatively-regulating target genes. In this thesis, we delineate mechanisms that demonstrate MBD2 is capable of binding a microRNA, mir-496, which is then capable of inducing itsiactivation. We further show that mir-496 can mediate a repressive action on three separate genes in the cell that have tumor suppressive roles in cancer. Chronic pain has been shown to alter gene expression and brain anatomy and is often accompanied with comorbidities that affect cognitive processing, sleep and anxiety. Interestingly, these changes have been shown to be reversible following effective treatment of pain, suggesting the mechanisms behind pain may also be reversible, thus prompting the study of pain epigenetics. We therefore proposed to test the hypothesis that the methylome and transcriptome are altered in the brain following peripheral nerve injury. We were able to identify a signature of DNA methylation and transcription specific to the prefrontal cortex and amygdala that accompanied peripheral nerve injury and behavioral signs of neuropathy. Furthermore we were able reverse behavioral signs of neuropathic pain and altered methylation states in the prefrontal cortex with environmental enrichment, demonstrating their reversible nature. Taken together, this thesis explores the role of DNA methylation in two complex diseases: through small scale processes in cancer and through broader changes at the level of the methylome and transcriptome in chronic pain. In identifying these molecular pathways and signatures, we hope to improve the mechanistic understanding of these pathologicaliistates, ultimately resulting in better treatment outcomes for millions of patients worldwide." --