title: A widespread role of the motif environment in transcription factor binding across diverse protein families.
abstract: Transcriptional regulation requires the binding of transcription factors (TFs) to short sequence-specific DNA motifs, usually located at the gene regulatory regions. Interestingly, based on a vast amount of data accumulated from genomic assays, it has been shown that only a small fraction of all potential binding sites containing the consensus motif of a given TF actually bind the protein. Recent in vitro binding assays, which exclude the effects of the cellular environment, also demonstrate selective TF binding. An intriguing conjecture is that the surroundings of cognate binding sites have unique characteristics that distinguish them from other sequences containing a similar motif that are not bound by the TF. To test this hypothesis, we conducted a comprehensive analysis of the sequence and DNA shape features surrounding the core-binding sites of 239 and 56 TFs extracted from in vitro HT-SELEX binding assays and in vivo ChIP-seq data, respectively. Comparing the nucleotide content of the regions around the TF-bound sites to the counterpart unbound regions containing the same consensus motifs revealed significant differences that extend far beyond the core-binding site. Specifically, the environment of the bound motifs demonstrated unique sequence compositions, DNA shape features, and overall high similarity to the core-binding motif. Notably, the regions around the binding sites of TFs that belong to the same TF families exhibited similar features, with high agreement between the in vitro and in vivo data sets. We propose that these unique features assist in guiding TFs to their cognate binding sites.
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel; Molecular and Computational Biology Program, Departments of Biological Sciences, Chemistry, Physics, and Computer Science, University of Southern California, Los Angeles, California 90089, USA;
authors.forename: Iris
authors.initials: I
authors.lastname: Dror
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Golan
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Carmit
authors.initials: C
authors.lastname: Levy
authors.affiliation: Molecular and Computational Biology Program, Departments of Biological Sciences, Chemistry, Physics, and Computer Science, University of Southern California, Los Angeles, California 90089, USA;
authors.forename: Remo
authors.initials: R
authors.lastname: Rohs
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel;
authors.forename: Yael
authors.initials: Y
authors.lastname: Mandel-Gutfreund
mesh_terms: D000818:Animals; D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods; D006801:Humans; D059372:Nucleotide Motifs; D050436:Regulatory Elements, Transcriptional; D012045:Regulatory Sequences, Nucleic Acid; D052156:SELEX Aptamer Technique; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors