DNA-mediated cooperativity facilitates the co-selection of cryptic enhancer sequences by SOX2 and PAX6 transcription factors

Kamesh Narasimhan, Shubhadra Pillay, Yong Heng Huang, Sriram Jayabal, Barath Udayasuryan, Veeramohan Veerapandian, Prasanna Kolatkar, Vlad Cojocaru, Konstantin Pervushin, Ralf Jauch

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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.

Original languageEnglish
Pages (from-to)1513-1528
Number of pages16
JournalNucleic Acids Research
Volume43
Issue number3
DOIs
Publication statusPublished - 2015

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ASJC Scopus subject areas

  • Genetics

Cite this

Narasimhan, K., Pillay, S., Huang, Y. H., Jayabal, S., Udayasuryan, B., Veerapandian, V., Kolatkar, P., Cojocaru, V., Pervushin, K., & Jauch, R. (2015). DNA-mediated cooperativity facilitates the co-selection of cryptic enhancer sequences by SOX2 and PAX6 transcription factors. Nucleic Acids Research, 43(3), 1513-1528. https://doi.org/10.1093/nar/gku1390