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Topological Properties of Eukaryotic Gene Regulatory Networks

Ouma, Zachary Wilberforce

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2017, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Understanding transcriptional regulation of gene expression on a genome-wide scale is predicated on deciphering interactions between all participating regulatory proteins and DNA. Advances in genomics are facilitating the high-throughput identification of these interactions, and graphs are emerging as indispensable tools for explaining how the connections in the network drive organismal phenotypic plasticity. In this work, I first present an investigative inquiry whose goal was to identify the source of unaligned sequence reads generated in studies aimed at identifying transcription factor binding sites (TFBSs). Determining TFBSs and the resulting architectures of gene regulatory networks (GRNs) relies on chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) methods. ChIP-Seq furnishes millions of short reads that, after alignment, describe the TFBSs of a particular transcription factor (TF). However, in all organisms investigated an average of 40% of reads fail to align to the corresponding genome, with some datasets having as much as 80% of reads failing to align. I describe here the provenance of previously unaligned reads in ChIP-Seq experiments from animals and plants. I show that a substantial portion corresponds to sequences of bacterial and metazoan origin, irrespective of the ChIP-Seq chromatin source. Unforeseen was the finding that 30% - 40% of unaligned reads were actually align-able. To validate these observations, I investigated the characteristics of the previously unaligned reads corresponding to TAL1, a human TF involved in lineage specification of hemopoietic cells. I show that, while unmapped ChIP-Seq read data sets contain foreign DNA sequences, additional TFBSs can be identified from the previously unaligned ChIP-Seq reads. These results indicate that the re-evaluation of previously unaligned reads from ChIP-Seq experiments contributes significantly to TF target identification and determination of emergent properties of GRNs. Secondly, I describe the architectural organization and associated emergent topological properties of GRNs that describe protein-DNA interactions (PDIs) in several model eukaryotes. By analyzing GRN connectivity, results presented here show that the anticipated scale-free network architectures are characterized by organism-specific power law scaling exponents. These exponents are independent of the fraction of the GRN experimentally sampled, enabling prediction of properties of the complete GRN for an organism. I further demonstrate that the exponents describe inequalities in TF-target gene recognition across GRNs. These observations have the important biological implication that they predict the existence of an intrinsic organism-specific trans and/or cis regulatory landscape that constrains GRN topologies. Consequently, architectural GRN organization drives not only phenotypic plasticity within a species, but is also likely implicated in species-specific phenotype. Lastly, I discuss future perspectives of this work. I briefly present models that can be used to capture GRN dynamics. I focus on a class of logical models— the Boolean network model, and propose a framework for constructing and implementing a dynamic model that captures the complex regulatory repertoire of eukaryotic organisms.
Richard Slotkin, PhD (Advisor)
Erich Grotewold, PhD (Committee Co-Chair)
Guramrit Singh, PhD (Committee Member)
Jeffrey Parvin , PhD (Committee Member)
Ralf Bundschuh, PhD (Committee Member)
177 p.

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Citations

  • Ouma, Z. W. (2017). Topological Properties of Eukaryotic Gene Regulatory Networks [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1512041623395438

    APA Style (7th edition)

  • Ouma, Zachary . Topological Properties of Eukaryotic Gene Regulatory Networks. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1512041623395438.

    MLA Style (8th edition)

  • Ouma, Zachary . "Topological Properties of Eukaryotic Gene Regulatory Networks." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1512041623395438

    Chicago Manual of Style (17th edition)