All ETDs from UAB

Advisory Committee Chair

Farah D Lubin

Advisory Committee Members

Michael Brenner

Michael Wyss

Lynn Dobrunz

Hengbin Wang

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Several studies have established the importance of epigenetic regulation of gene transcription in the brain during memory consolidation. Epigenetic mechanisms involve modifying the DNA or the associated histone proteins to determine the transcriptional outcome of a gene. The work encompassed in this dissertation serves as an initial investigation for the role of histone lysine methylation mechanisms in regulating gene activation and suppression in the medial temporal lobe that includes entorhinal cortex (EC), hippocampus, and amygdala during memory consolidation. To this end, we found that di-methylation of histone H3 at lysine 9 (H3K9me2) which promotes gene suppression was specific to associative learning in the amygdala and the EC. In addition, we found differential spatial and temporal regulation of histone methylation in the medial temporal lobe following acquisition. The histone lysine methyltransferase complex G9a/GLP (H/KMTs-G9a/GLP) mediates H3K9me2 formation. G9a/GLP was found to be critical for memory formation (MF) in hippocampus and the amygdala, and a negative regulator of MF in the EC. Interestingly, we found that a delicate balance between histone methylation mediated gene activation and suppression occurred during memory consolidation. Disruption of this balance in the EC revealed crosstalk between histone modifications during memory consolidation. Furthermore, we found H3K9me2 mediated molecular connectivity between the EC and the hippocampus during MF. Aberrant histone methylation at specific gene promoters contributes to the onset and development of mental illnesses. Hence, it's important to determine the sequence of signaling events orchestrating histone methylation changes within brain regions. We found that the GluN2B subunit of the NMDA receptor (NMDAR) regulates the recruitment of G9a/GLP and the antagonist histone lysine demethylase enzyme LSD1 (H/KDM-LSD1) in an ERK-dependent manner. In an attempt to identify a novel therapeutic locus for alleviating cognitive dysfunction associated with neurological disorders, we successfully rescued the memory deficits associated with hypo-functioning NMDARs by manipulating H3K9me2 levels within the amygdala. Overall, our findings begin to elucidate; first, the molecular mechanisms regulating histone methyltransferase and demethylase, second, histone methylation mediated regulation of gene transcription during MF, and third, emphasize the implementation of epigenetics as a powerful therapeutic tool in reversing gene dysregulation observed in neurological disorders.

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