PREMONition: An algorithm for predicting the circadian clock-regulated molecular network

A transcriptional feedback loop is central to clock function in animals, plants and fungi. The clock genes involved in its regulation are specific to - and highly conserved within - the kingdoms of life. However, other shared clock mechanisms, such as phosphorylation, are mediated by proteins found broadly among living organisms, performing functions in many cellular sub-systems. Use of homology to directly infer involvement/association with the clock mechanism in new, developing model systems, is therefore of limited use. Here we describe the approach PREMONition, PREdicting Molecular Networks, that uses functional relationships to predict molecular circadian clock associations. PREMONition is based on the incorporation of proteins encoded by known clock genes (when available), rhythmically expressed clock-controlled genes and non-rhythmically expressed but interacting genes into a cohesive network. After tuning PREMONition on the networks derived for human, fly and fungal circadian clocks, we deployed the approach to predict a molecular clock network for Saccharomyces cerevisiae , for which there are no readily-identifiable clock gene homologs. The predicted network was validated using gene expression data and a growth assay for sensitivity to light, a zeitgeber of circadian clocks of most organisms. PREMONition may be used to identify candidate clock-regulated processes and thus candidate clock genes in other organisms.