| Notes: | Advisor: Barton Wicksteed.
Thesis (Ph.D.)--The University of Chicago, Division of the Biological Sciences, and The Pritzker School of Medicine, Committee on Molecular Metabolism and Nutrition, 2015.
Dissertation Abstracts International, Volume: 76-08(E), Section: B.
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| Summary: | Our research aims to understand the epigenetic and transcriptional networks that direct gene expression to pancreatic [alpha] cells. DNA enhancer elements were identified in the [alpha] cell that are enriched in both enhancer associated-histone modifications and transcription factor binding. Approximately 25,000 regions of enrichment of both enhancer-associated histone modifications, H3K4me1 and H3K27Ac, were identified in an [alpha] cell line. In addition to histone modifications, transcription factors also associate with cell-type specific DNA enhancer elements. In the [alpha] cell line, separate ChIP-seq analysis of two transcription factors essential for [alpha] cell development and maintenance, Foxa2 and Nkx2.2, yielded 600 and 6,000 regions of enrichment found at enhancer sites in the [alpha] cell. Of these, 5 regions surrounding gene regions of [alpha] cell expressed genes showed potential to function in [alpha] cell enhancer activity. Expression analysis in zebrafish demonstrated these 3 of the 5 putative enhancer sequences were able to drive expression in the primary islets, but this expression was not restricted to the [alpha] cell. Additionally, Foxa2 binding was associated with all three sequences giving islet expression, and Nkx2.2 was bound to the enhancer that gave the strongest expression. The co-localization of these transcription factors to enhancer elements associated with genes highly expressed in [alpha] cells strongly indicates an important role for Foxa2 and Nkx2.2 in directing gene expression specifically to islet [alpha] cells.
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