| First Author | Kunitomi H | Year | 2026 |
| Journal | Cell Stem Cell | Volume | 33 |
| Issue | 6 | Pages | 1000-1015.e11 |
| PubMed ID | 42066769 | Mgi Jnum | J:389062 |
| Mgi Id | MGI:8331282 | Doi | 10.1016/j.stem.2026.04.006 |
| Citation | Kunitomi H, et al. (2026) eIF4G2-mediated selective translation of chromatin regulators safeguards adult intestinal stem cell identity and differentiation. Cell Stem Cell |
| abstractText | eIF4G2 (DAP5/NAT1) is a non-canonical translation initiation factor, but its role in homeostasis is unclear. Using inducible Eif4g2 knockout mice and intestinal organoids, we show that eIF4G2 loss collapses Lgr5(+) intestinal stem cell (ISC) and secretory maturation programs while preserving villus architecture. Transcriptomic and single-nucleus multiome analyses reveal a durable fetal-like/regenerative state with YAP-TEAD activation and regenerative absorptive cells. Ribosome profiling identifies selective translation-efficiency loss among chromatin regulators, especially the KAT3 coactivators CREBBP and EP300, resulting in reduced KAT3 abundance and global histone acetylation; chemical KAT3 inhibition phenocopies this state. CUT&Tag and assay for transposase-accessible chromatin sequencing (ATAC-seq) demonstrate that reduced eIF4G2-KAT3 output drives locus-selective enhancer remodeling, with loss of adult ISC/Wnt-Notch elements and activation of TEAD-enriched fetal loci, without inflammatory or integrated stress response programs driving the transition. Fetal intestinal spheroids remain viable despite similar biochemical defects, highlighting a stage-specific requirement for translational buffering in maintaining adult identity. |
