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

Mazzola, M. C.; Zhao, T.; Kiem, A.; Kristiansen, T. A.; Gustafsson, K.; Wong, L. P.; Scott-Solomon, E.; Fahlberg, M. D.; Forward, S.; Assita, E. R.; Schiroli, G.; Handley, M.; Kfoury, Y.; Fukushima, T.; Keyes, S.; Sharda, A.; Milosevic, J.; Kato, H.; Ivanov, P.; Sykes, D. B.; Kwok, S. J. J.; Sadreyev, R. I.; Sankaran, V. G.; Hsu, Y.-C.; Scadden, D. T.

doi:10.1101/2025.09.24.678136

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bioRxiv · 10.1101/2025.09.24.678136

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

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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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Mazzola, M. C., Zhao, T., Kiem, A., Kristiansen, T. A., Gustafsson, K., Wong, L. P., Scott-Solomon, E., Fahlberg, M. D., Forward, S., Assita, E. R., Schiroli, G., Handley, M., Kfoury, Y., Fukushima, T., Keyes, S., Sharda, A., Milosevic, J., Kato, H., Ivanov, P., Sykes, D. B., Kwok, S. J. J., Sadreyev, R. I., Sankaran, V. G., Hsu, Y.-C., Scadden, D. T.. 2025-09-25. Differentiation stage-specific use of cap-independent and cap-dependent translation initiation in hematopoiesis. https://doi.org/10.1101/2025.09.24.678136

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