Conversion of Sox17 into a pluripotency reprogramming factor by reengineering its association with Oct4 on DNA

Ralf Jauch, Irene Aksoy, Andrew Paul Hutchins, Calista Keow Leng Ng, Xian Feng Tian, Jiaxuan Chen, Paaventhan Palasingam, Paul Robson, Lawrence W. Stanton, Prasanna Kolatkar

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67 Citations (Scopus)

Abstract

Very few proteins are capable to induce pluripotent stem (iPS) cells and their biochemical uniqueness remains unexplained. For example, Sox2 cooperates with other transcription factors to generate iPS cells, but Sox17, despite binding to similar DNA sequences, cannot. Here, we show that Sox2 and Sox17 exhibit inverse heterodimerization preferences with Oct4 on the canonical versus a newly identified compressed sox/oct motif. We can swap the cooperativity profiles of Sox2 and Sox17 by exchanging single amino acids at the Oct4 interaction interface resulting in Sox2KE and Sox17EK proteins. The reengineered Sox17EK now promotes reprogramming of somatic cells to iPS, whereas Sox2KE has lost this potential. Consistently, when Sox2KE is overexpressed in embryonic stem cells it forces endoderm differentiation similar to wild-type Sox17. Together, we demonstrate that strategic point mutations that facilitate Sox/Oct4 dimer formation on variant DNA motifs lead to a dramatic swap of the bioactivities of Sox2 and Sox17.

Original languageEnglish
Pages (from-to)940-951
Number of pages12
JournalStem Cells
Volume29
Issue number6
DOIs
Publication statusPublished - 1 Jun 2011
Externally publishedYes

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Keywords

  • Endoderm differentiation
  • Induced pluripotent stem cells
  • Pluripotency
  • Reprogramming
  • Sox transcription factors

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Jauch, R., Aksoy, I., Hutchins, A. P., Ng, C. K. L., Tian, X. F., Chen, J., Palasingam, P., Robson, P., Stanton, L. W., & Kolatkar, P. (2011). Conversion of Sox17 into a pluripotency reprogramming factor by reengineering its association with Oct4 on DNA. Stem Cells, 29(6), 940-951. https://doi.org/10.1002/stem.639