Small Nucleolar RNA Snord17 Promotes Self‐Renewal of Intestinal Stem Cells through Yy2 mRNA Export and Tead4 Activation

The intestinal epithelium possesses a profound capacity for regeneration, which is fueled by the proliferation and differentiation of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5)-expressing intestinal stem cells (ISCs) located at the base of the crypts. However, how small nucleolar RNAs (snoRNAs) regulate the self-renewal of ISCs remains elusive. Here, we identified a small nucleolar RNA Snord17 that is highly expressed in ISCs. Snord17 knockout abrogates stemness of ISCs and impairs epithelial regeneration. Mechanistically, Snord17 interacts with THO complex 3 (Thoc3) to facilitate nuclear export of Yin yang 2 transcription factor (Yy2) mRNA for its subsequent translation. Yy2 protein enriches on the promoter of TEA domain family member 4 (Tead4) to activate its transcription, leading to activation of Hippo signaling for self-renewal maintenance of ISCs. Of note, Tead4 deficiency impairs self-renewal of ISCs and intestinal regeneration. Our findings reveal that the Snord17-Thoc3-Yy2-Tead4 axis is required for self-renewal maintenance of ISCs and gut regeneration.