Systems Biology Approaches to Probe Gene Regulation In Bacteria

<p>Mechanisms that allow pathogens to colonize the host are not the product of isolated genes, but instead emerge from the concerted operation of regulatory networks. Therefore, identifying components and the systemic behavior of networks is necessary to a better understanding of gene regulation and pathogenesis. To this end, I have developed systems biology approaches to study transcriptional and post-transcriptional gene regulation in bacteria, with an emphasis in the human pathogen <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>).</p> <p>First, I developed a network response method to identify parts of the <em>Mtb</em> global transcriptional regulatory network utilized by the pathogen to counteract phagosomal stresses and survive within resting macrophages. As a result, the method unveiled transcriptional regulators and associated regulons utilized by <em>Mtb</em> to establish a successful infection of macrophages throughout the first 14 days of infection. Additionally, this network-based analysis identified the production of Fe-S proteins coupled to lipid metabolism through the alkane hydroxylase complex as a possible strategy employed by <em>Mtb</em> to survive in the host.</p> <p>Second, I developed a network inference method to infer the small non-coding RNA (sRNA) regulatory network in <em>Mtb</em>. The method identifies sRNA-mRNA interactions by integrating <em>a priori</em> knowledge of possible binding sites with structure-driven identification of binding sites. The reconstructed network was useful to predict functional roles for the multitude of sRNAs recently discovered in the pathogen, being that several sRNAs were postulated to be involved in virulence-related processes.</p> <p>Finally, I applied a combined experimental and computational approach to study post-transcriptional repression mediated by small non-coding RNAs in bacteria. Specifically, a probabilistic ranking methodology termed rank-conciliation was developed to infer sRNA-mRNA interactions based on multiple types of data. The method was shown to improve target prediction in <em>Escherichia coli</em>, and therefore is useful to prioritize candidate targets for experimental validation.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2012

Author dc:creator

• Troggian Veiga, Diogo F

Contributors dc:contributor

• Gábor Balázsi
• Ambro van Hoof
• Tim Cooper

• Systems biology
• computational biology
• Mycobacterium tuberculosis
• Network analysis
• Gene regulation
• Bioinformatics
• Microbiology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/278

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1307