All ETDs from UAB

Advisory Committee Chair

Adam R Wende

Advisory Committee Members

Farah Lubin

Linda Overstreet-Wadiche

Craig M Powell

Nicole D Riddle

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) School of Medicine

Abstract

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is characterized by seizures originating from the temporal lobe of the brain. A frequent seizure focus in TLE is the hippocampus, a structure located within the temporal lobe crucial for its role in memory formation. Seizures are an excess of synchronous excitation in the brain caused by a surplus of excitatory neurotransmission and a lack of sufficient inhibitory transmission. Coordinating the process of neuronal transmission is differential expression of genes likely resulting in an increase or decrease in proteins responsible for neural signaling such as neurotransmitters, ion channels, and critical factors such as BDNF (brain-derived neurotrophic factor). These genes are actively regulated through epigenetic mechanisms such as DNA modifications, histone modifications, and noncoding RNAs rapidly turning the expression of genes on and off in response to inputs from the neuronal network. In this dissertation, I investigate the distribution of DNA Hydroxymethylation (5-hmC) in the epileptic rodent hippocampus. Through hmeDIPsequencing, we discover that 5-hmC is lost to a greater extent across the genome than the more regularly studied DNA 5-methylcytosine methylation (5-mC) and create a map of epigenetic 5-hmC loss. We find that the majority of 5-hmC loss occurs at intergenic iv regions, and identify differential methylation of genes involved in several epilepsyassociated pathways. In addition, we investigate the potential of epileptic differential DNA Hydroxymethylation (DhM) in the regulation of epileptic gene expression. We find that both hyper- and hypo- 5-hmC genes exhibit loss of gene expression, implicating the involvement of multiple gene regulatory mechanisms and cell types in 5-hmC control of epilepsy. We also investigate the histone H3k9me2 methyltransferase G9a in seizures. We find that conditional neuronal loss of G9a in the dentate gyrus leads to reduced seizure threshold in fl/fl KO animals and in fl/wt KD animals. This adds to evidence of the involvement of the H3k9me2 gene regulation pathway in seizure development and adds support to further investigation of G9a as a crucial seizure regulator.

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