Speaker: Edwin Wang Principles of microRNA Regulation of Cellular Networks According to the dogma of molecular biology, RNAs are passive messengers and take charge of transferring genetic information only. However, the dogma has been challenged by recent findings that microRNA (miRNA), a small non-coding RNA is able to negatively regulate protein-coding genes. miRNAs regulate gene expression at post-transcriptional level and translational level. A growing volume of evidence revealed that miRNAs are involved in a variety of biological processes. It is estimated that 10%-30% of genes might be regulated by miRNAs. The diversity and abundance of miRNA targets offer an enormous level of combinatorial possibilities and suggest that miRNAs and their targets appear to form a complex regulatory network intertwined with other cellular networks. However, it is unclear if and how miRNAs might orchestrate their regulation of cellular networks and how regulation of these networks might contribute to the biological functions of miRNAs. Here we address these questions by analyzing the interactions between miRNAs and human cellular networks including signaling, metabolic and gene regulatory networks1,2,3. We uncovered that in signaling networks, miRNAs predominantly target positive regulatory motifs, highly connected scaffolds and most downstream network components, but less frequently target negative regulatory motifs, common components of basic cellular machines and most upstream network components. In addition, when an adaptor has potential to recruit more downstream components, these components are more frequently targeted by miRNAs. These results imply that miRNAs have potential functions in facilitating robust transitions of cellular response to extracellular signals and maintaining cellular homeostasis. We also found that through preferentially targeting the network nodes with distinct network structural features, microRNA regulates metabolic networks globally, regionally and locally to reduce or block specific metabolite production in a way of fine-tuning or directly blocking metabolic flows. This work uncovers the principles of miRNA regulation of cellular networks and generates a set of testable hypotheses. References 1. Cui, Q., Yu, Z., Purisima, E., and Wang E., 2006, Principles of microRNA regulation of a human cellular signaling network, Molecular Systems Biology, in press. 2. Tibiche, C., MA. Shalu, Purisima, E., and Wang, E., 2006, MicroRNA regulatory strategies of metabolic networks, submitted. 3. Cui, Q., Yu, Z., Pan, Y., Purisima, E., and Wang E., 2006, MicoRNAs preferentially target the genes with high transcriptional regulation complexity, submitted.