Primate lineage specification requires suppression of Alu hyperediting

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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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-01-15
DOI
https://doi.org/10.64898/2026.01.14.699349
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
0.00
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article

Primate lineage specification requires suppression of Alu hyperediting

Florencia Levin-Ferreyra, Jorge Botas, Aryeh Warmflash, Yingzhi Cui et al.
bioRxiv (Cold Spring Harbor Laboratory)
RNA regulation and disease
article

Primate lineage specification requires suppression of Alu hyperediting

Florencia Levin-Ferreyra, Jorge Botas, Aryeh Warmflash, Yingzhi Cui, Lluís Morey, Núria Lupión-Garcia, Caroline M. Sands, Patrizia Pessina, Eric Van Nostrand, Michael S. Hoetker, Kateřina Čermáková, J. Wu, Robert F. Lera, Liyu Chen, Bruno Di Stefano, H. Courtney Hodges, Hao Wu, M. Cecilia Guerra, Víctor López Soriano, Emily J. Park
article en

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.

bioRxiv (Cold Spring Harbor Laboratory)
University of Wisconsin System (US), University of Wisconsin–Madison (US), University of Miami (US), Baylor College of Medicine (US), Heidelberg University (DE), University Hospital Heidelberg (DE), Morgridge Institute for Research (US), Quantitative BioSciences (US), Neurological Research Institute (US), Regenerative Medicine Institute (MX), Children's Cancer Center (US), Sylvester Comprehensive Cancer Center (US), Rice University (US), The University of Texas Southwestern Medical Center (US)
Openalex Percentile: Top 87%
RNA regulation and disease
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