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

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 Huynh, Michael R. O’Dwyer, Sonia Yiakoumi, Christos Spanos, Hazar Yassen, Keisuke Kaji, Hitoshi Niwa, Yosef Buganim, Sally Lowell and Abdenour Soufi ()
Additional contact information
Burak Ozkan: University of Edinburgh
Mitzy Rios Anda: University of Edinburgh
Elisa Hall-Ponsele: University of Edinburgh
Maria Rosa Portero Migueles: University of Edinburgh
Amani Alshaikh: University of Edinburgh
Marta Hanzevacki: University of Edinburgh
Moriyah Naama: The Hebrew University-Hadassah Medical School
Katharine Furlong: University of Edinburgh
Gareth A. Roberts: University of Edinburgh
Meryam Beniazza: University of Edinburgh
My Linh Huynh: University of Edinburgh
Michael R. O’Dwyer: 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
Yosef Buganim: The Hebrew University-Hadassah Medical School
Sally Lowell: University of Edinburgh
Abdenour Soufi: University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63806-3

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