Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm

Irene Aksoy, Ralf Jauch, Jiaxuan Chen, Mateusz Dyla, Ushashree Divakar, Gireesh K. Bogu, Roy Teo, Calista Keow Leng Ng, Wishva Herath, Sun Lili, Andrew P. Hutchins, Paul Robson, Prasanna R. Kolatkar, Lawrence W. Stanton

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

How regulatory information is encoded in the genome is poorly understood and poses a challenge when studying biological processes. We demonstrate here that genomic redistribution of Oct4 by alternative partnering with Sox2 and Sox17 is a fundamental regulatory event of endodermal specification. We show that Sox17 partners with Oct4 and binds to a unique 'compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at 'canonical' binding sites. The distinct selection of binding sites by alternative Sox/Oct partnering is underscored by our demonstration that rationally point-mutated Sox17 partners with Oct4 on pluripotency genes earmarked by the canonical Sox/Oct motif. In an endodermal differentiation assay, we demonstrate that the compressed motif is required for proper expression of endodermal genes. Evidently, Oct4 drives alternative developmental programs by switching Sox partners that affects enhancer selection, leading to either an endodermal or pluripotent cell fate. This work provides insights in understanding cell fate transcriptional regulation by highlighting the direct link between the DNA sequence of an enhancer and a developmental outcome.

Original languageEnglish
Pages (from-to)938-953
Number of pages16
JournalEMBO Journal
Volume32
Issue number7
DOIs
Publication statusPublished - 3 Apr 2013

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Keywords

  • Sox/Oct interaction
  • endoderm
  • enhancer code
  • lineage specification
  • pluripotency

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Aksoy, I., Jauch, R., Chen, J., Dyla, M., Divakar, U., Bogu, G. K., Teo, R., Leng Ng, C. K., Herath, W., Lili, S., Hutchins, A. P., Robson, P., Kolatkar, P. R., & Stanton, L. W. (2013). Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm. EMBO Journal, 32(7), 938-953. https://doi.org/10.1038/emboj.2013.31