RNA modification acts as an internal brake on stem cell growth
- Author：Kreeti Kajal, Elham Rastegari, Wen-Der Wang, Jian-Chiuan Li, Chun-Hong Chen, Wan-Hsuan Chou, Wei-Chiao Chang, Tzu-Yang Lin, Kevin Tsai, Tsai-Ming Lu, Kartik Venkatachalam and Hwei-Jan Hsu
- Journal： EMBO Reports https://link.springer.com/article/10.1038/s44319-026-00701-y
Wdr4 regulates ribosome biogenesis and intestinal homeostasis via let-7
Tight regulation of ribosome biogenesis is critical for stem cell function and tissue homeostasis, yet the upstream mechanisms governing this process in adult intestinal stem cells (ISCs) remain poorly understood. Here, we identify the WD repeat protein Wdr4 as a central regulator of ISC homeostasis in the Drosophila midgut. Wdr4 acts in concert with the methyltransferase Mettl1 to catalyse N7-methylguanosine (m7G) modification of the let-7 mRNA. Loss of Wdr4 or Mettl1 impairs this modification, leading to reduced let-7 abundance and aberrant activation of TOR-JNK-dMyc signaling. Consequently, ribosome biogenesis is elevated during ISC hyperproliferation, defective differentiation, and intestinal dysplasia. These phenotypes are reduced by let-7 overexpression, TOR inhibition, or JNK suppression. Notably, expression of human WDR4 and METTL1, but not kinase-dead METTL1 mutants, restores ISC homeostasis in Wdr4-or Mettl1-depleted flies, demonstrating evolutionary conservation of this pathway. Collectively, our findings define a conserved Wdr4/Mettl1-let7-TOR-JNK axis that couples miRNA m7G methylation to translation control, ribosome biogenesis, and intestinal tissue integrity.