Role of Transcription Factor-MicroRNA Feedback Circuits in the Canalization of Human Regulatory Networks

Abstract

Complex interactions between hundreds of transcription factors underlie the gene expression profiles that give rise to cellular form and function. However, it is still not entirely understood how organisms faithfully recapitulate complex phenotypes through differentiation and development. Here I discuss the role MicroRNAs play in the robustness of human gene regulatory networks. Specifically, I find that TF-miRNA negative feedback circuits are significantly enriched in networks across 156 diverse cell types and that the motifs occur preferentially with highly connected TFs that drive local network architecture. My work also implicates TF-miRNA circuits in the reinforcement of cell fate decisions, and expression changes observed during differentiation. Further to the aforementioned, a second aspect of my work has focused on approaches for targeted manipulation and perturbation of regulatory elements and networks. Although genome editing has now become commonplace, tools and approaches for precisely manipulating gene expression and regulatory networks are still lacking. Here I describe development of novel computational tools for the efficient design and synthesis of potent and specific Transcriptional Activator-Like Effectors (TALEs) and TALE nucleases (TALENs).