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BACKGROUND Many biological processes in mammals are subject to circadian control at the molecular level. Disruption of circadian rhythms has been demonstrated to be associated with a wide range of diseases, such as diabetes mellitus, mental disorders, and cancer. Although the core circadian genes are well established, there are multiple reports of novel peripheral circadian regulators. The goal of this study was to provide a comprehensive computational analysis to identify novel potential circadian transcriptional regulators. METHODS To fulfill the aforementioned goal, we applied a Boolean function network method to analyze the microarray time course mouse and rat liver datasets available in the literature. The inferred direct pairwise relations were further investigated using the functional annotation tool. This approach generated a list of transcription factors (TFs) and cofactors, which were associated with significantly enriched circadian gene ontology (GO) categories. RESULTS As a result, we identified 93 transcriptional circadian regulators in mouse and 95 transcriptional circadian regulators in rat. Of these, 19 regulators in mouse and 21 regulators in rat were known, whereas the rest were novel. Furthermore, we validated novel circadian TFs with bioinformatics databases, previous large-scale circadian studies, and related small-scale studies. Moreover, according to predictions inferred from ChIP-Seq experiments reported in the database, 40 of our candidate circadian regulators were confirmed to have circadian genes as direct regulatory targets. In addition, we annotated candidate circadian regulators with disorders that were often associated with disruptions of circadian rhythm in the literature. CONCLUSION In summary, our computational analysis, which was followed by an extensive verification by means of a literature review, can contribute to translational study from endocrinology to cancer research and provide insights for future investigation.

[This corrects the article DOI: 10.1371/journal.pone.0185475.].

The great amount of gene expression data has brought a big challenge for the discovery of Gene Regulatory Network (GRN). For network reconstruction and the investigation of regulatory relations, it is desirable to ensure directness of links between genes on a map, infer their directionality and explore candidate biological functions from high-throughput transcriptomic data. To address these problems, we introduce a Boolean Function Network (BFN) model based on techniques of hidden Markov model (HMM), likelihood ratio test and Boolean logic functions. BFN consists of two consecutive tests to establish links between pairs of genes and check their directness. We evaluate the performance of BFN through the application to S. cerevisiae time course data. BFN produces regulatory relations which show consistency with succession of cell cycle phases. Furthermore, it also improves sensitivity and specificity when compared with alternative methods of genetic network reverse engineering. Moreover, we demonstrate that BFN can provide proper resolution for GO enrichment of gene sets. Finally, the Boolean functions discovered by BFN can provide useful insights for the identification of control mechanisms of regulatory processes, which is the special advantage of the proposed approach. In combination with low computational complexity, BFN can serve as an efficient screening tool to reconstruct genes relations on the whole genome level. In addition, the BFN approach is also feasible to a wide range of time course datasets.