title: Discovery and validation of information theory-based transcription factor and cofactor binding site motifs.
abstract: Data from ChIP-seq experiments can derive the genome-wide binding specificities of transcription factors (TFs) and other regulatory proteins. We analyzed 765 ENCODE ChIP-seq peak datasets of 207 human TFs with a novel motif discovery pipeline based on recursive, thresholded entropy minimization. This approach, while obviating the need to compensate for skewed nucleotide composition, distinguishes true binding motifs from noise, quantifies the strengths of individual binding sites based on computed affinity and detects adjacent cofactor binding sites that coordinate with the targets of primary, immunoprecipitated TFs. We obtained contiguous and bipartite information theory-based position weight matrices (iPWMs) for 93 sequence-specific TFs, discovered 23 cofactor motifs for 127 TFs and revealed six high-confidence novel motifs. The reliability and accuracy of these iPWMs were determined via four independent validation methods, including the detection of experimentally proven binding sites, explanation of effects of characterized SNPs, comparison with previously published motifs and statistical analyses. We also predict previously unreported TF coregulatory interactions (e.g. TF complexes). These iPWMs constitute a powerful tool for predicting the effects of sequence variants in known binding sites, performing mutation analysis on regulatory SNPs and predicting previously unrecognized binding sites and target genes.
authors.affiliation: Department of Computer Science, Western University, London, Ontario, N6A 5B7, Canada.
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Biochemistry, Western University, London, Ontario, N6A 5C1, Canada.
authors.forename: Eliseos J
authors.initials: EJ
authors.lastname: Mucaki
authors.affiliation: Department of Computer Science, Western University, London, Ontario, N6A 5B7, Canada.|Department of Biochemistry, Western University, London, Ontario, N6A 5C1, Canada.|Department of Oncology, Western University, London, Ontario, N6A 4L6, Canada.|Cytognomix Inc., London, Ontario, N5X 3X5, Canada.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Rogan
mesh_terms: D001665:Binding Sites; D066264:Datasets as Topic; D019277:Entropy; D015894:Genome, Human; D006367:HeLa Cells; D006801:Humans; D007257:Information Theory; D020014:K562 Cells; D059372:Nucleotide Motifs; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014157:Transcription Factors