biostudies-literatureXu YChinese Academy of SciencesKey Technologies Research and Development ProgramNatural Science Foundation of Beijing MunicipalityChina Postdoctoral Science FoundationNational Natural Science Foundation of Chinae04485https://www.ebi.ac.uk/biostudies/studies/S-EPMC12667501biostudies-literatureUnknown12(44)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 stemAdvanced science (Weinheim, Baden-Wurttemberg, Germany)Snord15b Maintains Stemness of Intestinal Stem Cells via Enhancement of Alternative Splicing of Btrc Short Isoform for Suppression of β-Catenin Ubiquitination.PMC12667501821300885222023XDB05703012024M753424Z2311000072230132022YFF07107002020YFA0803501822717852020M6807122022T150685Li CFan ZDu YLan YZhang PXiong ZFan HGuo HTian YWu RZhu XWang ZXu YFan DfalseSnord15b Maintains Stemness of Intestinal Stem Cells via Enhancement of Alternative Splicing of Btrc 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 stem2025-01-01T00:00:00Z2025 Nov2026-06-05T21:03:58.643Z2026-05-21T03:13:00.424ZS-EPMC126675014088423310.1002/advs.202504485