Wdr4-mediated m7G modification on let-7 miRNA to Maintain Steady-State Ribosome Biogenesis for Intestinal Homeostasis

Ribosome biogenesis is recently known to control stem cell fate, while its role and regulation in intestinal stem cells (ISCs) remain unexplored. Here, we report that WD repeat protein 4 (Wdr4) complexes with Mettl1, an RNA methyltransferase, mediates m7G modification to preserve steady-state ribosome biogenesis in ISCs of the Drosophila midgut, functional equivalent to mammalian small intestines. Diminishing Wdr4 or Mettl1 elevates ribosome biogenesis, driving ISC overprolifaeration and misdifferentiation, leading to short lifespan. Mechanistically, Wdr4 or Mettl1 depletion in ISCs reduces m 7 G levels and let-7 expression, resulting in increased TOR signaling and ROS levels, which activate the JNK-dMyc signaling cascade. Concurrently, TOR signaling and dMyc enhance ribosome biogenesis. Furthermore, overexpression of human WDR4 and METTL1 in fly ISCs respectively restores the phenotypes caused by Wdr4 and Mettl1 loss, indicating a conserved role of m7G modification to maintain ISC homeostasis across species. Together, our findings unravel miRNA modulation in growth signaling and ribosome biogenesis for ISC homeostasis, offering new avenues for therapeutic interventions. RNA-seq profiling of wildtype and wdr4 mutant intestine of 7-day old drosophila