UBC Theses and Dissertations
Histone H3K4 methylation In hippocampal memory formation and In Alzheimer’s disease Obayashi, Yuka
Regulation of chromatin structure through posttranslational histone modifications is implicated in the induction of synaptic plasticity and memory formation. One such modification – histone H3 lysine 4 methylation (H3K4me) – has recently emerged as a key epigenetic modification necessary for consolidation of hippocampus-dependent memory. It is well-established that H3K4me levels across the genome are dynamically regulated by opposing activity of lysine methyltransferases (KMTs) and lysine demethylases (KDMs). They link dysregulation of H3K4 KMTs to neurodegenerative disorders, such as Alzheimer’s disease (AD). The major group of H3K4 KMTs in mammals are the Trithorax Group (TrxG) complexes, which can promote gene expression via distinct enzymatic (methylation of H3K4) and non-enzymatic (e.g. recruitment of other co-activators) mechanisms. In my project, I targeted the catalytic activity of TrxG complex and demonstrated that the loss of H3K4 methylation in mature hippocampal neurons leads to several intellectual abnormalities, such as the development of anxiety-like behaviour, recognition memory deficit, and impaired reversal memory with normal locomotory coordination in mice. Furthermore, I provided evidence of reduced H3K4 methylation in the hippocampus of AD by using a combination of patient samples and rodent disease model. Collectively, these results suggest that TrxG-mediated H3K4 methylation is required for a proper formation of hippocampal memory and may help shed light on H3K4 methylation as a novel therapeutic target for the treatment and prevention of AD.
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