| dc.description.abstract |
<p>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.</p>
|
|
