eIF4G2-mediated selective translation of chromatin regulators safeguards adult intestinal stem cell identity and differentiation.
Haruko Kunitomi, Aye Myat Khaine, Radia Jamee, Vanessa Arreola, Mariselle Lancero, Amba Raychaudhuri, Samuel Perli, Yoshiko Sato, Mio Iwasaki, Pedro Ruivo, Kiichiro Tomoda, Mari Mito, Yuichi Shichino, Shintaro Iwasaki, Shinya Yamanaka
Abstract
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.