2. Academic Validation
  3. An acidic residue within the OCT4 dimerization interface of SOX17 is necessary and sufficient to overcome its pluripotency-inducing activity

An acidic residue within the OCT4 dimerization interface of SOX17 is necessary and sufficient to overcome its pluripotency-inducing activity

  • Stem Cell Reports. 2025 Jan 23:102398. doi: 10.1016/j.stemcr.2025.102398.
Sik Yin Ho 1,  Haoqing Hu 2,  Derek Hoi Hang Ho 2,  Allan Patrick Stephane Renom 3,  Shi Wing Yeung 2,  Freya Boerner 4,  Mingxi Weng 5,  Andrew Paul Hutchins 6,  Ralf Jauch 7
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Laboratory for Primate Embryogenesis, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK.
  • 2 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Centre for Translational Stem Cell Biology, Hong Kong SAR, China.
  • 3 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 4 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Centre for Translational Stem Cell Biology, Hong Kong SAR, China; Faculty of Arts and Science, University of Toronto, Toronto, ON, Canada.
  • 5 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Altos Labs, San Diego, CA 92122, USA.
  • 6 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong Province 518055, China.
  • 7 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Centre for Translational Stem Cell Biology, Hong Kong SAR, China. Electronic address: ralf@hku.hk.
PMID: 39919754 DOI: 10.1016/j.stemcr.2025.102398
Abstract

SOX17 directs the differentiation toward endoderm and acts as a human germline specifier. We previously found that the replacement of glutamate at position 57 of the high-mobility group (HMG) box with the basic lysine residue in SOX2 alters interactions with OCT4 and turns SOX17 into a pluripotency factor. Here, we systematically interrogated how mutations at this critical position affect the cellular reprogramming activity of SOX17 in mouse and human. We found that most mutations turn SOX17 into a pluripotency factor regardless of their biophysical properties except for acidic residues and proline. The conservative mutation to an aspartate allows the SOX17E57D protein to maintain a self-renewing endodermal state. We showed that only the glutamate in the wild-type protein blocks the formation of an SOX17/OCT4 dimer at composite DNA elements in pluripotency enhancers. Insights into how modifications of an ultra-conserved residue affect functions of developmental transcription factors provide avenues to advance cell fate engineering.

Keywords

SOX17; SOX2; XEN; engineered proteins; iPSCs; pioneer factors; pluripotency; reprogramming.

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