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

## TL;DR

Snora54, a small nucleolar RNA, inhibits intestinal stem cell self-renewal and gut regeneration by suppressing Notch2 signaling through regulation of Lyar localization.

## Contribution

This study reveals a novel regulatory mechanism involving Snora54 and Lyar in controlling Notch2 signaling and ISC self-renewal.

## Key findings

- Snora54 knockout enhances intestinal stem cell self-renewal and gut regeneration.
- Snora54 suppresses Notch2 signaling by anchoring Lyar in the nucleolus.
- Deletion of Snora54 allows Lyar to activate Notch2 transcription in the nucleoplasm.

## 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.

Snora54 inhibits Notch2 signaling by regulating the nuclear localization of Lyar, thereby negatively regulating ISC self-renewal.