All ETDs from UAB

Advisory Committee Chair

Farah D Lubin

Advisory Committee Members

Trygve O Tollefsbol

Erik D Roberson

Robin G Lorenz

Sarah M Clinton

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Epigenetic mechanisms such as DNA methylation and histone methylation are critical regulators of gene transcription during memory consolidation and retrieval. However, the means by which these mechanisms are themselves initiated and directed to specific gene regions, and the extent to which these marks coordinate control of gene expression, remain poorly understood. In this dissertation, we explore the role of methyl-lysine signaling in the epigenetic regulation of gene expression in two contexts. First, we investigated the role of histone H3 lysine 4 tri-methylation (H3K4me3) and DNA 5-hydroxymethylation (5hmC) during memory retrieval, finding that these marks increased globally and at CpG-enriched coding regions of memory-related genes, though at different genes and in different regions depending on whether the memory retrieved was recent or remote. These findings suggest time-dependent and region-specific changes in transcriptional control during the memory retrieval. Using siRNA to knockdown the H3K4me3 methyltransferase Mll1 in the CA1, we showed that ablation of normal H3K4me3 abolished retrieval-induced changes in DNA 5hmC and impaired memory, providing new evidence of crosstalk between histone methylation and DNA 5hmC during memory retrieval. Turning to the mechanisms by which epigenetic processes are initiated, we next identified the lysine methyltransferase SETD6 as a critical regulator of epigenetic control in long-term memory, specifically through its methylation of nuclear factor kappa B (NF-κB) RELA and associated histone methylation in CA1 during memory consolidation. We show that these changes correlate with increases in histone H3 lysine 9 dimethylation (H3K9me2) and lead to changes in gene expression, dendritic spine morphology, and memory behavior. These findings suggest that SETD6 is an upstream initiator of H3K9me2 changes in the hippocampus during memory consolidation. Together, this research makes novel contributions to our understanding of the epigenetic control of long-term memory formation and elucidates the role of methyl-lysine signaling in initiating and coordinating these mechanisms.

Share

COinS