title: Finding subtypes of transcription factor motif pairs with distinct regulatory roles.
abstract: DNA sequences bound by a transcription factor (TF) are presumed to contain sequence elements that reflect its DNA binding preferences and its downstream-regulatory effects. Experimentally identified TF binding sites (TFBSs) are usually similar enough to be summarized by a 'consensus' motif, representative of the TF DNA binding specificity. Studies have shown that groups of nucleotide TFBS variants (subtypes) can contribute to distinct modes of downstream regulation by the TF via differential recruitment of cofactors. A TF(A) may bind to TFBS subtypes a(1) or a(2) depending on whether it associates with cofactors TF(B) or TF(C), respectively. While some approaches can discover motif pairs (dyads), none address the problem of identifying 'variants' of dyads. TFs are key components of multiple regulatory pathways targeting different sets of genes perhaps with different binding preferences. Identifying the discriminating TF-DNA associations that lead to the differential downstream regulation is thus essential. We present DiSCo (Discovery of Subtypes and Cofactors), a novel approach for identifying variants of dyad motifs (and their respective target sequence sets) that are instrumental for differential downstream regulation. Using both simulated and experimental datasets, we demonstrate how current motif discovery can be successfully leveraged to address this question.
authors.affiliation: Department of Computational and Systems Biology, Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine and Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Abha Singh
authors.initials: AS
authors.lastname: Bais
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Panayiotis V
authors.initials: PV
authors.lastname: Benos
mesh_terms: D000465:Algorithms; D001483:Base Sequence; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000378:metabolism; D016384:Consensus Sequence; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D050436:Regulatory Elements, Transcriptional; D017422:Sequence Analysis, DNA; D012984:Software; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D050882:CREB-Binding Protein