title: PRISM offers a comprehensive genomic approach to transcription factor function prediction.
abstract: The human genome encodes 1500-2000 different transcription factors (TFs). ChIP-seq is revealing the global binding profiles of a fraction of TFs in a fraction of their biological contexts. These data show that the majority of TFs bind directly next to a large number of context-relevant target genes, that most binding is distal, and that binding is context specific. Because of the effort and cost involved, ChIP-seq is seldom used in search of novel TF function. Such exploration is instead done using expression perturbation and genetic screens. Here we propose a comprehensive computational framework for transcription factor function prediction. We curate 332 high-quality nonredundant TF binding motifs that represent all major DNA binding domains, and improve cross-species conserved binding site prediction to obtain 3.3 million conserved, mostly distal, binding site predictions. We combine these with 2.4 million facts about all human and mouse gene functions, in a novel statistical framework, in search of enrichments of particular motifs next to groups of target genes of particular functions. Rigorous parameter tuning and a harsh null are used to minimize false positives. Our novel PRISM (predicting regulatory information from single motifs) approach obtains 2543 TF function predictions in a large variety of contexts, at a false discovery rate of 16%. The predictions are highly enriched for validated TF roles, and 45 of 67 (67%) tested binding site regions in five different contexts act as enhancers in functionally matched cells.
authors: Department of Computer Science, Stanford University, Stanford, California 94305, USA.
authors: Aaron M
authors: AM
authors: Wenger
authors: Shoa L
authors: SL
authors: Clarke
authors: Harendra
authors: H
authors: Guturu
authors: Jenny
authors: J
authors: Chen
authors: Bruce T
authors: BT
authors: Schaar
authors: Cory Y
authors: CY
authors: McLean
authors: Gill
authors: G
authors: Bejerano
mesh_terms: D000465:Algorithms; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics*; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics; D016678:Genome; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D012984:Software; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors
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