DNA-mediated Cooperativity Facilitates the Co-selection of Cryptic Enhancer Sequences by SOX2 and PAX6 Transcription Factors

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2015 Jan 13

PMID 25578969

Citations 22

Authors

Kamesh Narasimhan

Shubhadra Pillay

Yong-Heng Huang

Sriram Jayabal

Barath Udayasuryan

Veeramohan Veerapandian

Prasanna Kolatkar

Vlad Cojocaru

Konstantin Pervushin

Ralf Jauch

Affiliations

Soon will be listed here.

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.

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