Insights into the Regulatory Activities of Chromatin ThroughComputational Analyses of Whole-Genome Data
2013
In the last decade, advances in DNA sequencing
technology have enabled the routine generation of whole-genome
datasets that profile chromatin composition and conformation.
Quantitative analyses of these data have required the development
of innovative computational data analysis methodologies. These
analysis techniques have been used to generate novel biological
hypotheses about the regulatory activities of chromatin, which can
be experimentally validated. This dissertation presents several
case studies of such analyses. In the first study, machine learning
models, which predict transcription as a function of multivariate
histone modification levels, are used to predict the association of
symmetrically dimethylated arginine 3 on histone H4 (H4R3me2s) with
transcriptional repression. Methodological approaches to
constructing similar models are also explored in depth. In the next
study, analyses of changes in a panel of histone modifications
during the epithelial-mesenchymal transition (EMT) reveal a high
degree of regulatory coordination among genes within distinct
functional classes and pathways. Changes at enhancers associated
with these genes also show coordination with respect to
transcription factor binding. These observations lead to the
hypothesis that histone modifications enable and sustain
transcriptional feedback loops distinctly associated with each
phenotypic endpoint in EMT. In the final study, a novel approach
for analyzing unbiased chromatin interaction data (Hi-C data) is
presented. This approach utilizes network analysis techniques to
infer conformational features of the genome. Using these
techniques, assessments are made of the degree of hierarchical
organization in the budding yeast genome. Furthermore, a novel
correlation between replication timing and degree of
inter-chromosomal interactions is observed. The studies presented
in this dissertation demonstrate the utility of computational data
analysis in generating novel systems-level hypotheses about the
regulatory behavior of chromatin. Since many of the analysis
techniques presented in this work have not been otherwise applied
to chromatin data, many domain-specific technical considerations
are also discussed. This dissertation provides a variety of novel
insights into the regulatory activities of chromatin; and perhaps
more importantly, it provides several analytical frameworks for
distilling systems-level insights from whole-genome chromatin
data.
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