Predicting combinatorial binding of transcription factors to regulatory elements in the human genome by association rule mining

Support for most pairs of transcription factor binding motifs was highly correlated across different chromosomes although pair significance varied. Known true positive motif pairs showed higher association rule support, confidence, and significance than background. Our subsets of high-confidence, high-significance mined pairs of transcription factors showed enrichment for co-citation in PubMed abstracts relative to all pairs, and the predicted associations were often readily verifiable in the literature.Functional elements in the genome where transcription factors bind to regulate expression in a combinatorial manner are more likely to be predicted by identifying statistically and biologically significant combinations of transcription factor binding motifs than by simply scanning the genome for the occurrence of binding sites for a single transcription factor.Substantial differences of phenotype can be primarily the result of differences in gene expression levels rather than in protein structure. Genes are dynamically regulated, primarily at the transcriptional level, by protein transcription factors that bind DNA at cis-regulatory regions to activate or repress expression. Mammalian cis-regulatory regions range in length from the 60 bp human muSK enhancer [1] to the 450 bp human TGFβ enhancer [2] to the 1100 bp enhancer of murine Pax6 [3], but they are generally a few hundred base pairs in length. Enhancers contain binding sites for transcription factors, sometimes for a single factor and sometimes for many [4]. A detailed understanding of the transcriptional regulatory programs of any organism requires knowledge of the binding sites of transcription factors, the circumstances and cellular conditions under which these transcription factors bind to their targets, and the genes that are regulated by combinations of transcription factors.Cis-regulatory regions for most of the approximately 20,000 protein-coding genes encoded in the human genome have not yet been chara