title: DNA-dependent formation of transcription factor pairs alters their binding specificity.
abstract: Gene expression is regulated by transcription factors (TFs), proteins that recognize short DNA sequence motifs. Such sequences are very common in the human genome, and an important determinant of the specificity of gene expression is the cooperative binding of multiple TFs to closely located motifs. However, interactions between DNA-bound TFs have not been systematically characterized. To identify TF pairs that bind cooperatively to DNA, and to characterize their spacing and orientation preferences, we have performed consecutive affinity-purification systematic evolution of ligands by exponential enrichment (CAP-SELEX) analysis of 9,400 TF-TF-DNA interactions. This analysis revealed 315 TF-TF interactions recognizing 618 heterodimeric motifs, most of which have not been previously described. The observed cooperativity occurred promiscuously between TFs from diverse structural families. Structural analysis of the TF pairs, including a novel crystal structure of MEIS1 and DLX3 bound to their identified recognition site, revealed that the interactions between the TFs were predominantly mediated by DNA. Most TF pair sites identified involved a large overlap between individual TF recognition motifs, and resulted in recognition of composite sites that were markedly different from the individual TF's motifs. Together, our results indicate that the DNA molecule commonly plays an active role in cooperative interactions that define the gene regulatory lexicon.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden.
authors.forename: Arttu
authors.initials: A
authors.lastname: Jolma
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden.
authors.forename: Kazuhiro R
authors.initials: KR
authors.lastname: Nitta
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden.
authors.forename: Kashyap
authors.initials: K
authors.lastname: Dave
authors.affiliation: European Synchrotron Radiation Facility, 38043 Grenoble, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Popov
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden.
authors.forename: Minna
authors.initials: M
authors.lastname: Taipale
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Enge
authors.affiliation: Genome-Scale Biology Program, University of Helsinki, P.O. Box 63, FI-00014, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Kivioja
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Morgunova
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden.|Genome-Scale Biology Program, University of Helsinki, P.O. Box 63, FI-00014, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs / Q000235:genetics; D015203:Reproducibility of Results; D013379:Substrate Specificity / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D004247:DNA