title: A novel unbiased measure for motif co-occurrence predicts combinatorial regulation of transcription.
abstract: BACKGROUND
  Multiple transcription factors (TFs) are involved in the generation of gene expression patterns, such as tissue-specific gene expression and pleiotropic immune responses. However, how combinations of TFs orchestrate diverse gene expression patterns is poorly understood. Here we propose a new measure for regulatory motif co-occurrence and a new methodology to systematically identify TF pairs significantly co-occurring in a set of promoter sequences.
  
  
  RESULTS
  Initial analyses suggest that non-CpG promoters have a higher potential for combinatorial regulation than CpG island-associated promoters, and that co-occurrences are strongly influenced by motif similarity. We applied our method to large-scale gene expression data from various tissues, and showed how our measure for motif co-occurrence is not biased by motif over-representation. Our method identified, amongst others, the binding motifs of HNF1 and FOXP1 to be significantly co-occurring in promoters of liver/kidney specific genes. Binding sites tend to be positioned proximally to each other, suggesting interactions exist between this pair of transcription factors. Moreover, the binding sites of several TFs were found to co-occur with NF-κB and IRF sites in sets of genes with similar expression patterns in dendritic cells after Toll-like receptor stimulation. Of these, we experimentally verified that CCAAT enhancer binding protein alpha positively regulates its target promoters synergistically with NF-κB.
  
  
  CONCLUSIONS
  Both computational and experimental results indicate that the proposed method can clarify TF interactions that could not be observed by currently available prediction methods.
authors.affiliation: Laboratory of Systems Immunology, Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. alexisvdb@ifrec.osaka-u.ac.jp
authors.forename: Alexis
authors.initials: A
authors.lastname: Vandenbon
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
mesh_terms: D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D018899:CpG Islands; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D016678:Genome; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D051538:Hepatocyte Nuclear Factor 1-alpha; D016328:NF-kappa B; D012097:Repressor Proteins; D051193:Toll-Like Receptors; D014157:Transcription Factors