<i>Snord15b</i> Maintains Stemness of Intestinal Stem Cells via Enhancement of Alternative Splicing of <i>Btrc</i> Short Isoform for Suppression of β‐Catenin Ubiquitination

Intestinal epithelium is derived from Lgr5⁺ intestinal stem cells (ISCs) located at the crypt base. However, how small nucleolar RNAs (snoRNAs) regulate ISC stemness remains elusive. Here, a conserved snoRNA, Snord15b, that is highly expressed in ISCs is identified. Snord15b knockout abolishes the self-renewal capacity of ISCs and impairs epithelial regeneration. Mechanistically, Snord15b interacts with interleukin enhancer-binding factor 2 (Ilf2) to recruit splicing factors, which mediates alternative splicing of Btrc to form a short isoform of Btrc, resulting in abrogation of E3 ligase complex formation for ubiquitination of β-catenin. Subsequently, stable β-catenin translocates into the nucleus of ISCs for activation of the Wnt/β-catenin signaling pathway, leading to ISC stemness maintenance and intestinal regeneration. Of note, knockout of Snord15b or Ilf2 increases β-catenin ubiquitination to suppress activation of Wnt signaling. Furthermore, Btrc knockout blocks β-catenin ubiquitination to enhance the stemness of ISCs and intestinal regeneration. These findings reveal that Snord15b-Ilf2 association mediates alternative splicing of Btrc short isoform to inhibit β-catenin ubiquitination for ISC stemness maintenance.