<i>Snora54</i> negatively regulates self-renewal of intestinal stem cells and gut regeneration via suppression of Notch2 signaling

The self-renewal of intestinal stem cells (ISCs) is essential for maintaining intestinal homeostasis and ensuring regeneration of the intestinal epithelium. However, whether small nucleolar RNAs participate in the regulation of ISC self-renewal remains unclear. Here, we identified a small nucleolar RNA (<i>Snora54</i>) that was highly expressed in the nucleolus of ISCs. <i>Snora54</i> knockout enhanced the self-renewal capacity of ISCs and intestinal regeneration. Mechanistically, in a steady state, highly expressed <i>Snora54</i> anchored the nucleolar protein Lyar in the nucleolus of ISCs, preventing Lyar from translocation into the nucleoplasm. Thereby, Lyar failed to recruit on the <i>Notch2</i> promoter region in the nucleoplasm to promote <i>Notch2</i> transcription, leading to suppression of ISC self-renewal. By contrast, with deletion of <i>Snora54</i>, Lyar translocated to the nucleoplasm of ISCs where it enriched on the <i>Notch2</i> promoter to initiate its transcription resulting in the activation of Notch2 signaling pathway. Therefore, <i>Snora54</i> negatively regulates self-renewal of ISCs and gut regeneration via suppression of Notch2 signaling.