Shifting IRES versus Cap-initiated translation during homeostatic stem cell differentiation and stress
G) 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.
Authors
- Jelena Milosevic (ORCID: https://orcid.org/0000-0001-7062-2276)
- Vijay G. Sankaran (ORCID: https://orcid.org/0000-0003-0044-443X)
- Giulia Schiroli (ORCID: https://orcid.org/0000-0002-9812-8728)
- Emily Scott-Solomon (ORCID: https://orcid.org/0000-0002-7018-2132)
- Christina Mayerhofer (ORCID: https://orcid.org/0000-0002-5755-1458)
- Michael Mazzola (ORCID: https://orcid.org/0000-0002-3000-7997)
- Ernst Mayerhofer (ORCID: https://orcid.org/0000-0001-8902-4209)
- Sarah Forward
- Tsuyoshi Fukushima (ORCID: https://orcid.org/0000-0002-9350-777X)
- Samuel Keyes
- Marissa Fahlberg (ORCID: https://orcid.org/0000-0002-2597-7147)
- Sheldon J. J. Kwok (ORCID: https://orcid.org/0000-0001-7880-0401)
- Anna Kiem (ORCID: https://orcid.org/0009-0005-1177-1374)
- Ya‐Chieh Hsu (ORCID: https://orcid.org/0000-0002-0178-7373)
- Youmna Kfoury
- Lai Ping Wong
- Ting Zhao
- Karin Gustafsson
- Azeem Sharda
- Hiroki Kato (ORCID: https://orcid.org/0000-0002-4021-3356)
- David T. Scadden (ORCID: https://orcid.org/0000-0001-9821-7133)
- Dan Li (ORCID: https://orcid.org/0000-0002-6332-1093)
- Trine A. Kristiansen
- Ruslan I. Sadreyev (ORCID: https://orcid.org/0000-0002-4240-5466)
- Maris Handley
- David B. Sykes (ORCID: https://orcid.org/0000-0002-9788-0221)
- Emane Rose Assita
- Pavel Ivanov
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Harvard Affiliated Emergency Medicine Residency (US)
- Dana-Farber Cancer Institute (US)
- BVI (United States) (US)
- Harvard Stem Cell Institute (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1126/sciadv.adz7896
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Vetenskapsrådet