Chromatin Accessibility Dynamics Underlying Development and Disease

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2015

Authors

Frank, Christopher L.

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Abstract

Despite a largely static DNA sequence, our genomes are incredibly malleable. Comparative studies of chromatin features between different cell types, tissues, and species have revealed tremendous differences in how the genome is accessed, transcribed, and replicated. However, how the dynamics of chromatin accessibility contribute to development, environmental response, and disease status has only begun to be appreciated. In this work we identified chromatin accessibility changes by DNase-seq in three diverse processes: in granule neurons of the developing cerebellum, with intestinal epithelial cells in the absence of a normal microbiota, and with myelogenous leukemia cells in response to histone deacetylase inhibitor treatments. In all cases, we coupled these analyses with RNA-seq assays to identify concurrent transcriptional changes. By mapping the changes to these genome-wide signals we defined the contribution of local chromatin structure to the transcriptional programs underlying these processes, and improved our understanding of their relation to other chromatin changes like histone modifications. Furthermore we demonstrated use of the strongest accessibility changes to identify transcription factors critical for these processes by finding enrichment of their binding motifs. For a few of these key factors, depletion or overexpression of the protein was sufficient to regulate the expression of predicted target genes or exert limited chromatin accessibility changes, demonstrating the functional significance of these proteins in these processes. Together these studies have informed our understanding of the role chromatin accessibility changes play in development and environmental responses while also proving their utility for key regulator identification.

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Frank, Christopher L. (2015). Chromatin Accessibility Dynamics Underlying Development and Disease. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/11359.

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