Abstract
Intestinal epithelium relies on intestinal stem cells (ISCs) for rapid and precise tissue replenishment to maintain gut normal function. The self-renewal maintenance of ISCs is finely regulated by multiple stemness factors and signaling pathways. However, the transcription mechanisms of some key stemness factors remain poorly understood. Here, we identify that small nucleolar RNA Snora61 is highly expressed in ISCs. Snora61 is mainly distributed in the nucleoplasm. Snora61 knockout impairs ISC self-renewal and intestinal regeneration. Mechanistically, Snora61 binds to the promoter region of Lgr5 gene and engages with RNA-binding protein RBMX to recruit HMGB2 onto Lgr5 promoter, leading to Lgr5 transcription and expression. Snora61 promotes the self-renewal of small intestinal stem cells, which in turn enhances the proliferation of differentiated epithelial cells, thereby contributing to the maintenance of intestinal homeostasis. Conversely, Snora61 knockout causes reduced LGR5 expression. Deletion of Lgr5 with Snora61 displays more severely impaired ISC self-renewal and intestinal regeneration. Our findings reveal a regulatory mechanism of Lgr5 transcription underlying ISC self-renewal maintenance.
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Data availability
The raw RNA sequence data reported in this paper have been deposited in the Genome Sequence Archive in National Genomics Data Center, China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences under accession codes CRA026331, CRA033390, CRA033391, and CRA033396. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository with the dataset identifier PXD070722. The raw ChIRP-seq data have been deposited in the GEO database (GSE315692) that have been publicly accessible at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE315692. The remaining data are available within the Article, Supplementary Information, or Source Data file. All full uncropped blots for every associated figure are available in the source data file, with light dotted lines indicating the areas presented in the figures. Source data are provided in this paper. Source data are provided with this paper.
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Acknowledgements
We thank Y. Xu, X. Ding, G. Hou and J. Jia for technical support. We thank Jing Li (Cnkingbio Company Ltd, Beijing, China) for technical assistance. This work was supported by National Natural Science Foundation of China (82530038, 82130088, 82271785); National Key R&D Program of China (2020YFA0803501); Natural Science Foundation of Beijing (Z231100007223013); the Young Elite Scientist Sponsorship Program by CAST of China (2023QNRC001) and Strategic Priority Research Programs of the Chinese Academy of Sciences (XDB0570000).
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J.H., Y.L. and Y.X. performed experiments; J.H. designed the project, analyzed the data and wrote the paper. Y.L., Y.X., Z.X., Z.Y., H.G, J.Z., Z.Z. Y.D. and F.P. provided technical assistance and analyzed data; Z.F. initiated the study, organized, designed, and wrote the paper.
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He, J., Lan, Y., Xu, Y. et al. Small nucleolar RNA Snora61 drives self-renewal of intestinal stem cells via initiation of Lgr5 transcription. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71620-8
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DOI: https://doi.org/10.1038/s41467-026-71620-8
