MicroRNA Regulatory Patterns on the Human Metabolic Network

MicroRNA (miRNA) is an emerging class of non-coding small RNAs, which post-transcriptionally regulate a large number of genes and become important regulators of a broad spectrum of biological processes. To understand the principles of miRNA regulation of metabolic networks, we systematically analyzed the relationships between miRNA targets and network nodes (enzymes) which have distinct network structural features through mapping the miRNA targets onto a human metabolic network. Our analysis showed that miRNAs preferentially regulate hub nodes, i.e., top 5% of the highly connected nodes in the network, and the network cut points which are the bottle-necks of metabolic flows, however, avoid regulating intermediate nodes which are the nodes between the hub nodes, cut points, upstream nodes and the output nodes. Furthermore, two or three consecutive linear metabolic reactions in the network are enriched with miRNA targets, while metabolic branches are depleted with miRNA targets. By targeting the network nodes with distinct network structural features, miRNA regulates metabolic networks regionally and locally to reduce specific metabolite production in a way of fine-tune modulating metabolic flows. Functional association analysis of miRNAs and metabolic pathways uncovered that miRNAs predominantly regulate central metabolic pathways such as amino acid biosynthesis, certain sugar and lipid metabolism.