Fungus to fibroblast: a functional genomic exploration of eukaryotic transcriptional regulation

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Title: Fungus to fibroblast: a functional genomic exploration of eukaryotic transcriptional regulation
Author: Killion, Patrick J., 1974-
Abstract: I have pursued a breadth of research that explored the functional genomic study of eukaryotic transcriptional regulation . I have utilized two model organisms , many experimental methodologies , and have developed a suite of computational resources to study the interaction of transcription factors with regulated targets . In Saccharomyces cerevisiae I worked with my collaborator Dr . Zhanzhi (Mike ) Hu to characterize the whole -genome transcriptional response of 263 individual transcription factor deletions . We utilized a sophisticated error model and directed -weighted graphs to model a network of high -confidence targets for each transcription factor profiled . We then used regulatory epistasis to elucidate the true set of primary KO -regulated targets and construct a functional transcriptional regulatory network . This network was analyzed for ontological and sequence motif enrichment in order to gain insight into the biological functions represented by transcription factors studied . Functional validation was performed to evaluate the probability of novel functional characterizations . Significant insight was gained from this study with regard to the nature of regulatory cascades and the inability for DNA binding events to predict regulation . This set of analysis was performed with a novel bioinformatic server called ArrayPlex . ArrayPlex is a software package that centrally provides a large number of flexible toolsets useful for functional genomics including microarray data storage , quality assessments , data visualization , gene annotation retrieval , statistical tests , genomic sequence retrieval and motif analysis . It uses a client -server architecture based on open source components , provides graphical , command -line , as well as programmatic access to all needed resources , and is extensible by virtue of a documented API . Using many of the techniques and computational resources developed , I pursued the study of microRNA transcriptional abundance and targeting in H . sapiens cell cultures . Utilizing custom -fabricated microarrays , I measured the whole -genome response of both mRNAs and microRNAs under serum stimulation , c -Myc overexpression , and c -Myc siRNA -mediated knockdown . I then characterized the regulatory interactions between the sets of regulated microRNAs and coordinately regulated transcription factors . Using analytical methods sensitive to regulatory directionality of both populations I was able to determine high -confidence relationships between transcription factors and regulated microRNAs as well as microRNAs and regulated gene targets .
URI: http : / /hdl .handle .net /2152 /3616
Date: 2008-08-28

Citation

Fungus to fibroblast: a functional genomic exploration of eukaryotic transcriptional regulation. Doctoral dissertation, The University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /3616 .

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