title: DNA-mediated cooperativity facilitates the co-selection of cryptic enhancer sequences by SOX2 and PAX6 transcription factors.
abstract: Sox2 and Pax6 are transcription factors that direct cell fate decision during neurogenesis, yet the mechanism behind how they cooperate on enhancer DNA elements and regulate gene expression is unclear. By systematically interrogating Sox2 and Pax6 interaction on minimal enhancer elements, we found that cooperative DNA recognition relies on combinatorial nucleotide switches and precisely spaced, but cryptic composite DNA motifs. Surprisingly, all tested Sox and Pax paralogs have the capacity to cooperate on such enhancer elements. NMR and molecular modeling reveal very few direct protein-protein interactions between Sox2 and Pax6, suggesting that cooperative binding is mediated by allosteric interactions propagating through DNA structure. Furthermore, we detected and validated several novel sites in the human genome targeted cooperatively by Sox2 and Pax6. Collectively, we demonstrate that Sox-Pax partnerships have the potential to substantially alter DNA target specificities and likely enable the pleiotropic and context-specific action of these cell-lineage specifiers.
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Kamesh
authors.initials: K
authors.lastname: Narasimhan
authors.affiliation: Genome Regulation Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Shubhadra
authors.initials: S
authors.lastname: Pillay
authors.affiliation: Laboratory for Structural Biochemistry, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Yong-Heng
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada Integrated Program in Neuroscience, McGill University, Montreal, Quebec H3G 0B1, Canada.
authors.forename: Sriram
authors.initials: S
authors.lastname: Jayabal
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Barath
authors.initials: B
authors.lastname: Udayasuryan
authors.affiliation: Laboratory for Structural Biochemistry, Genome Institute of Singapore, Singapore 138672, Singapore University of Chinese Academy of Sciences, No. 19A Yuquanlu, Beijing 100049, China.
authors.forename: Veeramohan
authors.initials: V
authors.lastname: Veerapandian
authors.affiliation: Qatar Biomedical Research Institute, Qatar Foundation, PO Box 5825, Doha, Qatar.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Kolatkar
authors.affiliation: Computational Structural Biology Laboratory, Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster 48149, Germany.
authors.forename: Vlad
authors.initials: V
authors.lastname: Cojocaru
authors.affiliation: Genome Regulation Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Pervushin
authors.affiliation: Laboratory for Structural Biochemistry, Genome Institute of Singapore, Singapore 138672, Singapore ralf@gibh.ac.cn.
authors.forename: Ralf
authors.initials: R
authors.lastname: Jauch
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000502:physiology*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic; D005136:Eye Proteins / Q000737:chemistry / Q000502:physiology*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000737:chemistry / Q000502:physiology*; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D004247:DNA