2. Academic Validation
  3. Differentiation stage-specific use of cap-independent and cap-dependent translation initiation in hematopoiesis

Differentiation stage-specific use of cap-independent and cap-dependent translation initiation in hematopoiesis

  • bioRxiv. 2025 Sep 25:2025.09.24.678136. doi: 10.1101/2025.09.24.678136.
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,  Sarah Forward 6,  Emane Rose Assita 6,  Giulia Schiroli 1 2 3,  Maris Handley 1 7,  Youmna Kfoury 1 2 3,  Tsuyoshi Fukushima 1 2 3,  Samuel Keyes 1 2 3,  Azeem Sharda 1 2 3,  Jelena Milosevic 1 2 3,  Hiroki Kato 1 2 3,  Pavel Ivanov 8 9 10,  David B Sykes 1 2,  Sheldon J J Kwok 6,  Ruslan I Sadreyev 4 5,  Vijay G Sankaran 2 11 12 13,  Ya-Chieh Hsu 2 3,  David T Scadden 1 2 3
Affiliations

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 HSCI-CRM Flow Cytometry Core Facility, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
  • 8 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 9 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 10 Harvard Initiative for RNA Medicine, Boston, MA 02115, USA.
  • 11 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 12 Division of Hematology / Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 13 Howard Hughes Medical Institute, Boston, MA, USA.
PMID: 41040404 DOI: 10.1101/2025.09.24.678136
Abstract

Cell stress can increase the use of m7G-cap-independent, 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 modulation of translation initiation participates in cell differentiation state.

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