Date of Award

Summer 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Genomics & Computational Biology

First Advisor

Sridhar Hannenhalli

Second Advisor

Stephen R. Master

Abstract

The spatiotemporal coordination of gene expression is a fundamental process in cellular biology. Gene expression is regulated, in large part, by sequence-specific transcription factors that bind to DNA regions in the proximity of each target gene. Transcription factor activity and specificity are, in turn, regulated post-translationally by protein-modifying enzymes. High-throughput methods exist to probe specific steps of this process, such as protein-protein and protein-DNA interactions, but few computational tools exist to integrate this information in a principled, model-oriented manner. In this work, I develop several computational tools for studying the functional implications of transcription factor modification. I establish the first publicly accessible database for known and predicted regulatory circuits that encompass modifying enzymes, transcription factors, and transcriptional targets. I also develop a model-based method for integrating heterogeneous genomic and proteomic data for the inference of modification-dependent transcriptional regulatory networks. The model-based method is thoroughly validated as a reliable and accurate computational genomic tool. Additionally, I propose and demonstrate fundamental improvements to computational proteomic methods for identifying modified protein forms. In summary, this work contributes critical methodological advances to the field of regulatory network inference.

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