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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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    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Hong Sook Kim & Yuliang Tan & Wubin Ma & Daria Merkurjev & Eugin Destici & Qi Ma & Tom Suter & Kenneth Ohgi & Meyer Friedman & Dorota Skowronska-Krawczyk & Michael G. Rosenfeld, 2018. "Pluripotency factors functionally premark cell-type-restricted enhancers in ES cells," Nature, Nature, vol. 556(7702), pages 510-514, April.
    3. Xiaodong Liu & John F. Ouyang & Fernando J. Rossello & Jia Ping Tan & Kathryn C. Davidson & Daniela S. Valdes & Jan Schröder & Yu B. Y. Sun & Joseph Chen & Anja S. Knaupp & Guizhi Sun & Hun S. Chy & Z, 2020. "Reprogramming roadmap reveals route to human induced trophoblast stem cells," Nature, Nature, vol. 586(7827), pages 101-107, October.
    4. Daniel F. Kaemena & Masahito Yoshihara & Meryam Beniazza & James Ashmore & Suling Zhao & Mårten Bertenstam & Victor Olariu & Shintaro Katayama & Keisuke Okita & Simon R. Tomlinson & Kosuke Yusa & Keis, 2023. "B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Rachel Tsunemoto & Sohyon Lee & Attila Szűcs & Pavel Chubukov & Irina Sokolova & Joel W. Blanchard & Kevin T. Eade & Jacob Bruggemann & Chunlei Wu & Ali Torkamani & Pietro Paolo Sanna & Kristin K. Bal, 2018. "Diverse reprogramming codes for neuronal identity," Nature, Nature, vol. 557(7705), pages 375-380, May.
    6. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    7. Bálint Mészáros & István Simon & Zsuzsanna Dosztányi, 2009. "Prediction of Protein Binding Regions in Disordered Proteins," PLOS Computational Biology, Public Library of Science, vol. 5(5), pages 1-18, May.
    8. Thomas Graf & Tariq Enver, 2009. "Forcing cells to change lineages," Nature, Nature, vol. 462(7273), pages 587-594, December.
    9. Moriyah Naama & Moran Rahamim & Valery Zayat & Shulamit Sebban & Ahmed Radwan & Dana Orzech & Rachel Lasry & Annael Ifrah & Mohammad Jaber & Ofra Sabag & Hazar Yassen & Areej Khatib & Silvina Epsztejn, 2023. "Pluripotency-independent induction of human trophoblast stem cells from fibroblasts," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    10. Laurie A. Boyer & Kathrin Plath & Julia Zeitlinger & Tobias Brambrink & Lea A. Medeiros & Tong Ihn Lee & Stuart S. Levine & Marius Wernig & Adriana Tajonar & Mridula K. Ray & George W. Bell & Arie P. , 2006. "Polycomb complexes repress developmental regulators in murine embryonic stem cells," Nature, Nature, vol. 441(7091), pages 349-353, May.
    11. Julie Carnesecchi & Gianluca Sigismondo & Katrin Domsch & Clara Eva Paula Baader & Mahmoud-Reza Rafiee & Jeroen Krijgsveld & Ingrid Lohmann, 2020. "Multi-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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