Date

June 2012

Document Type

Thesis

Degree Name

M.S.

Department

Dept. of Medical Informatics and Clinical Epidemiology

Institution

Oregon Health & Science University

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that are responsible for posttranscriptional gene silencing. These miRNAs are associated with the RISC (RNA-Induced Silencing Complex) that uses a seed sequence to target specific genes. Both expression of miRNAs and genes within virus-infected cells provide independent data in identifying biological hypotheses concerning regulation changes during infection. To do this, three data types are available for integration: gene expression microarray, miRNA expression microarray and RISC-Immunoprecipitation (RISC-IP) microarray. RISC-IP data provides a look at what genes are associated with the complex during infection versus uninfected cells (mock). Incorporating three independent data types allows a more complete representation of host response to Flavivirus infection that is key to identifying miRNA regulators. This thesis integrates all three types of data for Flavivirus-infected cells using the statistical programming environment R to identify statistically enriched miRNAs regulating host response. First, the integration of gene expression changes and enriched RISC-associated genes identify significant miRNA regulators overlapping with miRNA expression data. Dengue gene expression was found to have a significant positive association with one or more differentially expressed miRNAs. More specifically, Dengue-infected cells’ up-regulated genes are significantly associated with down-regulated miRNAs. No significant associations were found in West Nile-infected cells. Results suggest evidence Dengue gene expression and miRNA expression are complementary and suggests that miRNAs and genes are being co-regulated during infection. Secondly, regulatory networks were built using differentially expressed genes as identifiers of statistically common miRNA regulators between West Nile and Dengue network modules. Comparing all Dengue modules with all West Nile gene network modules, 20 of 114 comparisons contained miRNA regulators statistically significantly overlapping. Eight miRNAs regulate these modules: hsa-let-7b, hsa-miR-1, hsa-miR-124,hsa-miR-155, hsa-miR-16, hsa-miR-29c, hsa-miR-30, and hsa-miR-373. These miRNAs, common to both Dengue and West Nile regulatory networks, suggest co-regulation of genes that are changing during host response to infection. Focusing on more informative miRNAs, those regulating genes during infection, will direct experimental research efforts to key miRNAs for experimental validation with the end-goal of guiding gene therapy and non-viral drug development in hopes to reduce the number of Flavivirus induced deaths.

Identifier

doi:10.6083/M4862DFX

School

School of Medicine

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