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UBC Theses and Dissertations

Metabolic regulation of chromatin structure and gene expression in beta-cells from mice fed a western diet Bégin, Jocelyn Adele


Background: The deposition and removal of histone modifications are dictated by the intracellular levels of metabolites produced during cellular metabolism. Metabolites of interest include; S-adenosylmethionine (SAM), the key methyl donor for histone methylation; and S-adenosylhomocysteine (SAH), produced following methyl donation. Histone modifications, in turn, regulate gene expression. Dysregulation of β-cell metabolism in type 2 diabetes (T2D) may impact the levels of key metabolites, resulting in pathological alterations of chromatin state and gene expression. I hypothesize that β-cells from a diet-induced mouse model of T2D will have altered levels of key metabolites required as co-factors for chromatin-modifying enzymes, which will alter histone modifications at key β-cell gene loci and produce a pathological gene expression pattern. Methods: Using a diet-induced mouse model of T2D (western diet, WD) I performed transcriptomic and epigenetic analysis in β-cells from male and female mice fed a WD or a control diet (CD). I compared enrichment and combinational patterns of histone modifications across the β-cell genome and at differentially expressed genes (DEGs). I also examined SAM and SAH concentrations in islets. Results: Contrary to my hypothesis, islet SAM and SAH concentrations were not different between male and female WD and CD mice. The β-cell transcriptomes of WD mice had multiple DEGs to control mice. Expression of genes associated with oxidative phosphorylation were lower in WD mice. Genes associated with histone demethylation were upregulated in WD females, but not observed in WD males. Levels of H3K4me1 were greater, and H3K4me3 and H3K27ac/me3 were lower in WD mice. Based on the combination of the four histone modifications, chromatin states were annotated at the promoters of the DEGs and compared between WD and CD mice. A positive relationship between chromatin state and gene expression was identified, with higher active chromatin states at promoters of genes with higher expression, and lower active chromatin states at promoters of genes with lower expression in WD mice compared to control mice. Conclusion: The histone modification landscapes within β-cells were dramatically changed in a diet-induced mouse model of T2D and are related to gene expression profiles but are unrelated to SAM and SAH concentrations.

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