Figure 4
Application of ModuleMiner to microarray clusters. (a) The two-step procedure used to detect similar cis-regulatory modules (CRMs) in a subset of genes within a given microarray cluster. In the first step, a fivefold cross-validation is performed, and the number of left-out genes considered as target genes is counted. If this number is significantly more than expected under a random distribution of the ranks, then these genes are transferred to the second step. In this second step, ModuleMiner is used to model the similar CRMs regulating the genes in this focused subcluster. (b) Results of the first step of the procedure in panel (a) for the ten microarray clusters and the three different sets of candidate transcription factor binding sites (TFBSs). Significantly higher numbers of target genes among the left-out genes than randomly expected are depicted by an asterisk. Clusters 7 and 10 only contained sufficient genes (≥ 25) in TFBS set 3 and therefore are omitted for the other two sets. (c) Leave-one-out cross-validation results on the subclusters with a significant enrichment of target genes from panel (b). Each left-out gene was ranked using the transcriptional regulatory global model (TRGM) obtained on the remaining genes. Next, sensitivity/specificity pairs where calculated for different detection thresholds, and these were used to construct receiver operating characteristic (ROC) curves. The areas under these ROC curves (AUCs) were calculated and are depicted here. The colors are as in panel (b). (d) Presented is an example of a set of similar CRMs identified by ModuleMiner. These results were obtained on the cardiac muscle genes by the procedure depicted in panel (a). Each horizontal line represents a human-mouse conserved noncoding sequence (CNS) upstream of a gene within the cluster. The different colored boxes represent binding sites of different transcription factors. Detailed results, including descriptions of the genes shown, and the exact positions of the CNSs are available on our website [26].