Understanding Regulatory Mechanisms Underlying Stem Cells Helps to Identify Cancer Biomarkers

Detection of biomarker genes play a crucial role in disease detection and treatment. Bioinformatics offers a variety of approaches for identification of biomarker genes which play key roles in complex diseases. These computational approaches enhance the insight derived from experiments and reduce the efforts of biologists and experimentalists. This is essentially achieved through prioritizing a set of genes with certain attributes. In this thesis, we show that understanding the regulatory mechanisms underlying stem cells helps to identify cancer biomarkers. We got inspired by the regulatory mechanisms of the pluripotency network in mouse embryonic stem cells and formulated the problem where a set of master regulatory genes in regulatory networks is identified with two combinatorial optimization problems namely as minimum dominating set and minimum connected dominating set in weakly and strongly connected components. Then we applied the developed methods to regulatory cancer networks to identify disease-associated genes and anti-cancer drug targets in breast cancer and hepatocellular carcinoma. As not all the nodes in the solutions are critical, we developed a prioritization method to rank a set of candidate genes which are related to a certain disease based on systematic analysis of the genes that are differentially expressed in tumor and normal conditions. Moreover, we demonstrated that the topological features in regulatory networks surrounding differentially expressed genes are highly consistent in terms of using the output of several analysis tools. We compared two randomization strategies for TF-miRNA co-regulatory networks to infer significant network motifs underlying cellular identity. We showed that the edge-type conserving method surpasses the non-conserving method in terms of biological relevance and centrality overlap. We presented several web servers and software packages that are publicly available at no cost. The Cytoscape plugin of minimum connected dominating set identifies a set of key regulatory genes in a user provided regulatory network based on a heuristic approach. The ILP formulations of minimum dominating set and minimum connected dominating set return the optimal solutions for the aforementioned problems. Our source code is publicly available. The web servers TFmiR and TFmiR2 construct disease-, tissue-, process-specific networks for the sets of deregulated genes and miRNAs provided by a user. They highlight topological hotspots and offer detection of three- and four-node FFL motifs as a separate web service for both organisms mouse and human