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Cell-type-specific functionality encoded within the intrinsically disordered regions of OCT4

Author

Listed:
  • Burak Ozkan

    (University of Edinburgh
    University of Edinburgh)

  • Mitzy Rios Anda

    (University of Edinburgh
    University of Edinburgh)

  • Elisa Hall-Ponsele

    (University of Edinburgh
    University of Edinburgh)

  • Maria Rosa Portero Migueles

    (University of Edinburgh)

  • Amani Alshaikh

    (University of Edinburgh
    University of Edinburgh
    King Abdulaziz City for Science and Technology Health Sector)

  • Marta Hanzevacki

    (University of Edinburgh
    University of Edinburgh)

  • Moriyah Naama

    (The Hebrew University-Hadassah Medical School)

  • Katharine Furlong

    (University of Edinburgh
    University of Edinburgh)

  • Gareth A. Roberts

    (University of Edinburgh
    University of Edinburgh)

  • Meryam Beniazza

    (University of Edinburgh)

  • My Linh Huynh

    (University of Edinburgh)

  • Michael R. O’Dwyer

    (University of Edinburgh
    University of Edinburgh)

  • Sonia Yiakoumi

    (University of Edinburgh)

  • Christos Spanos

    (Wellcome Discovery Research Platform for Hidden Cell Biology, Michael Swann Building)

  • Hazar Yassen

    (The Hebrew University-Hadassah Medical School)

  • Keisuke Kaji

    (University of Edinburgh)

  • Hitoshi Niwa

    (Kumamoto University
    RIKEN Center for Developmental Biology)

  • Yosef Buganim

    (The Hebrew University-Hadassah Medical School)

  • Sally Lowell

    (University of Edinburgh
    University of Edinburgh)

  • Abdenour Soufi

    (University of Edinburgh
    University of Edinburgh)

Abstract

The cell-type-specific function of transcription factors (TFs) is crucial for determining cellular identity. However, it is unclear how a single TF can function specifically in different cell types. Here, we define the molecular features that enable OCT4 to reprogram somatic cells into pluripotent or trophoblast stem cells, maintain the self-renewal of embryonic stem cells (ESCs), and drive lineage commitment during early embryonic development. Embedded within the intrinsically disordered regions (IDRs) of OCT4, we uncover short linear peptides that are essential for reprogramming (SLiPERs) but dispensable for ESC self-renewal. SLiPERs adopt a quasi-ordered state and, during reprogramming, recruit a unique set of proteins to closed chromatin that are unnecessary for ESC self-renewal. Interestingly, SLiPERs are essential for embryos to develop beyond late gastrulation. Removing SLiPERs leads to aberrant OCT4 binding, derailing the regular transition of ESCs out of pluripotency. Our findings identify modules within IDRs that contribute to the functional versatility and specificity of TFs.

Suggested Citation

  • Burak Ozkan & Mitzy Rios Anda & Elisa Hall-Ponsele & Maria Rosa Portero Migueles & Amani Alshaikh & Marta Hanzevacki & Moriyah Naama & Katharine Furlong & Gareth A. Roberts & Meryam Beniazza & My Linh, 2025. "Cell-type-specific functionality encoded within the intrinsically disordered regions of OCT4," Nature Communications, Nature, vol. 16(1), pages 1-26, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63806-3
    DOI: 10.1038/s41467-025-63806-3
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