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

Abstract

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 (Snora54) that was highly expressed in the nucleolus of ISCs. Snora54 knockout enhanced the self-renewal capacity of ISCs and intestinal regeneration. Mechanistically, in a steady state, highly expressed Snora54 anchored the nucleolar protein Lyar in the nucleolus of ISCs, preventing Lyar from translocation into the nucleoplasm. Thereby, Lyar failed to recruit on the Notch2 promoter region in the nucleoplasm to promote Notch2 transcription, leading to suppression of ISC self-renewal. By contrast, with deletion of Snora54, Lyar translocated to the nucleoplasm of ISCs where it enriched on the Notch2 promoter to initiate its transcription resulting in the activation of Notch2 signaling pathway. Therefore, Snora54 negatively regulates self-renewal of ISCs and gut regeneration via suppression of Notch2 signaling.