Co-option of ILF2/3 in primates restrains Alu hyper-editing to enable cell fate transitions

Park, E. J.; Cui, Y.; Levin-Ferreyra, F.; Soriano, V. L.; Wu, H.; Lupion-Garcia, N.; Sands, C. M.; Pessina, P.; Guerra, M. C.; Botas, J.; Chen, L.-Y.; Cermakova, K.; Hodges, H. C.; Morey, L.; Coon, J. J.; Wu, J.; Warmflash, A.; Van Nostrand, E.; Hoetker, M. S.; Di Stefano, B.

doi:10.64898/2026.01.14.699349

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bioRxiv · 10.64898/2026.01.14.699349

Co-option of ILF2/3 in primates restrains Alu hyper-editing to enable cell fate transitions

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Abstract

Understanding human specific mechanisms of cell fate control is essential for advancing developmental biology and regenerative medicine. Here, we identify the ILF2/3 complex as a critical regulator of primate cell fate transitions. Using genetically and epigenetically engineered gastruloids and adult stem cells, we show that ILF2/3 is required for gastrulation in primates but not mice, and for differentiation of adult progenitor cells. Mechanistically, ILF2/3 directly binds Alu elements in chromatin-associated RNAs and shields them from ADAR1-mediated adenosine-to-inosine (A-to-I) editing. Acute ILF2/3 degradation increases A-to-I editing at Alu elements, but not murine retrotransposons, leading to aberrant splicing and nonsense-mediated decay of transcripts encoding key chromatin regulators in primate cells. This in turn destabilizes the epigenetic landscape and blocks lineage commitment across all three germ layers. Re-expression of correctly spliced chromatin regulators rescues differentiation defects in ILF2/3-deficient cells, functionally linking Alu editing control to chromatin regulation and cell fate. These findings define an evolutionary mechanism that restrains retrotransposon-associated RNA editing to preserve proteome integrity and enable primate-specific developmental programs.

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Park, E. J., Cui, Y., Levin-Ferreyra, F., Soriano, V. L., Wu, H., Lupion-Garcia, N., Sands, C. M., Pessina, P., Guerra, M. C., Botas, J., Chen, L.-Y., Cermakova, K., Hodges, H. C., Morey, L., Coon, J. J., Wu, J., Warmflash, A., Van Nostrand, E., Hoetker, M. S., Di Stefano, B.. 2026-01-15. Co-option of ILF2/3 in primates restrains Alu hyper-editing to enable cell fate transitions. https://doi.org/10.64898/2026.01.14.699349

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