Detecting cooperativity between transcription factors based on functional coherence and similarity of their target gene sets

In eukaryotic cells, transcriptional regulation of gene expression is usually achieved by cooperative transcription factors (TFs). Therefore, knowing cooperative TFs is the first step toward uncovering the molecular mechanisms of gene expression regulation. Many algorithms based on different rationales have been proposed to predict cooperative TF pairs in yeast. Although various types of rationales have been used in the existing algorithms, functional coherence is not yet used. This prompts us to develop a new algorithm based on functional coherence and similarity of the target gene sets to identify cooperative TF pairs in yeast. The proposed algorithm predicted 40 cooperative TF pairs. Among them, three (Pdc2-Thi2, Hot1-Msn1 and Leu3-Met28) are novel predictions, which have not been predicted by any existing algorithms. Strikingly, two (Pdc2-Thi2 and Hot1-Msn1) of the three novel predictions have been experimentally validated, demonstrating the power of the proposed algorithm. Moreover, we show that the predictions of the proposed algorithm are more biologically meaningful than the predictions of 17 existing algorithms under four evaluation indices. In summary, our study suggests that new algorithms based on novel rationales are worthy of developing for detecting previously unidentifiable cooperative TF pairs.