Shifting IRES versus Cap-initiated translation during homeostatic stem cell differentiation and stress

  • Sci Adv. 2026 May 22;12(21):eadz7896. doi: 10.1126/sciadv.adz7896.
Michael C Mazzola  1  2  3 ,  Ting Zhao  1  2  3 ,  Anna Kiem  1  2  3 ,  Trine A Kristiansen  1  2  3 ,  Karin Gustafsson  1  2  3 ,  Lai Ping Wong  4  5 ,  Emily Scott-Solomon  2  3 ,  Marissa D Fahlberg  6 ,  Christina Mayerhofer  1  2  3 ,  Ernst Mayerhofer  7  8 ,  Sarah Forward  6 ,  Emane Rose Assita  6 ,  Giulia Schiroli  1  2  3 ,  Maris Handley  1  9 ,  Youmna Kfoury  1  2  3 ,  Tsuyoshi Fukushima  1  2  3 ,  Dan Li  1  2  3 ,  Samuel Keyes  1  2  3 ,  Azeem Sharda  1  2  3 ,  Jelena Milosevic  1  2 ,  Hiroki Kato  1  2  3 ,  Pavel Ivanov  10  11  12 ,  David B Sykes  1  2 ,  Sheldon J J Kwok  6 ,  Ruslan I Sadreyev  4  5 ,  Vijay G Sankaran  2  12  13  14 ,  Ya-Chieh Hsu  2  3 ,  David T Scadden  1  2  3
Affiliations
  • 1. Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
  • 2. Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 02138, USA.
  • 3. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • 4. Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
  • 5. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • 6. LASE Innovation Inc., 335 Bear Hill Road, Waltham, MA 02451, USA.
  • 7. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02115, USA.
  • 8. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 9. HSCI-CRM Flow Cytometry Core Facility, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
  • 10. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 11. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 12. Harvard Initiative for RNA Medicine, Boston, MA 02115, USA.
  • 13. Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 14. Howard Hughes Medical Institute, Boston, MA 02115, USA.
PMID: 42172329 DOI: 10.1126/sciadv.adz7896
Abstract

Cell stress can increase the use of methylated guanosine (m7G) cap-independent, internal ribosome entry site (IRES)-mediated translation initiation relative to cap-dependent translation (IRES/Cap). Reporters that quantify IRES/Cap have demonstrated differential activity across cultured cell types and stress conditions. By generating an IRES/Cap reporter mouse, we were able to systematically evaluate IRES/Cap across distinct tissues and cell types during physiological stresses and lineage commitment. Caloric stress invoked the expected boost in IRES/Cap translation regardless of differentiation state, but unexpectedly, IRES/Cap progressively increased during hematopoietic and epithelial (hair follicle) differentiation under normal, homeostatic conditions. This was independent of total protein output or cell cycle. Even within cells of a given differentiation state, cells with lower relative IRES utilization had markedly higher multipotent capability in vivo. The RNA processing protein PTBP1 is a mediator of this translation initiation preference. Therefore, low IRES/Cap is a signature of high stemness and suggests that modulation of translation initiation participates in cell differentiation state.

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