Analyzing Differential Regulatory Networks Modulated by Continuous-State Genomic Features in Glioblastoma Multiforme

Yu-Chiao Chiu, Tzu-Hung Hsiao, Li-Ju Wang, Yidong Chen, Eric Y. Chuang

Gene regulatory networks are a global representation of complex interactions between molecules that dictate cellular behavior. Study of a regulatory network modulated by single or multiple modulators' expression levels, including microRNAs (miRNAs) and transcription factors (TFs), in different conditions can further reveal the modulators' roles in diseases such as cancers. Existing computational methods for identifying such modulated regulatory networks are typically carried out by comparing groups of samples dichotomized with respect to the modulator status, ignoring the fact that most biological features are intrinsically continuous variables. Here we devised a sliding window-based regression scheme and proposed the Regression-based Inference of Modulation (RIM) algorithm to infer the dynamic gene regulation modulated by continuous-state modulators. We demonstrated the improvement in performance as well as computation efficiency achieved by RIM. Applying RIM to genome-wide expression profiles of 520 glioblastoma multiforme (GBM) tumors, we investigated miRNA- and TFmodulated gene regulatory networks and showed their association with dynamic cellular processes and brain-related functions in GBM. Overall, the proposed algorithm provides an efficient and robust scheme for comprehensively studying modulated gene regulatory networks.