A network biology study on circadian rhythm by integrating various omics data.

Circadian rhythm is fundamentally important in physiological processes of mammals. To reveal its underlying mechanism, we probed functional interactions among genes, motivated by the basic molecular observation on gene expression data in circadian rhythm that a large number of genes oscillate in a coordinated manner. In this study, a reverse-engineering strategy was applied to infer and analyze the structure and function of a circadian rhythm-related gene regulatory network. Specifically, our method integrated four phase-shift time-course gene expression datasets in rat suprachiasmatic nucleus, protein-protein interactions, phosphorylations of a set of key circadian genes, and prior information of cis-regulatory elements, to construct the gene regulatory network related to circadian rhythm of the rat. By follow-up analysis, we identified four new regulatory hubs that may play crucial roles in the regulation of circadian rhythm. Furthermore, we found that feedback loop motifs were significantly enriched in the predicted network, which may contribute to the genome-wide oscillations of the circadian clock. Compared to the small-scale gene regulatory network conducted by experimental method, our study provides a system-wide overview on the gene regulations, which not only reveals the global network structure but also gives valuable insights into the essential mechanism of circadian rhythm.