2. Academic Validation
  3. DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells

DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells

  • Nat Commun. 2024 Apr 9;15(1):3080. doi: 10.1038/s41467-024-47235-2.
Xingxing Ren 1 2 3,  Qiuyuan Liu 4,  Peirong Zhou 3,  Tingyue Zhou 2,  Decai Wang 2,  Qiao Mei 4,  Richard A Flavell 5 6,  Zhanju Liu 7,  Mingsong Li 8,  Wen Pan 9 10,  Shu Zhu 11 12 13
Affiliations

Affiliations

  • 1 Hefei National Research Center for Physical Sciences at the Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, China.
  • 2 Key Laboratory of immune response and immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 3 Department of Gastroenterology, Third Affiliated Hospital of Guangzhou Medical University, 510145, Guangzhou, China.
  • 4 Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 5 Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 6 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 7 Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. zhanjuliu@tongji.edu.cn.
  • 8 Department of Gastroenterology, Third Affiliated Hospital of Guangzhou Medical University, 510145, Guangzhou, China. lims661216@163.com.
  • 9 Hefei National Research Center for Physical Sciences at the Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, China. wenpan@ustc.edu.cn.
  • 10 Key Laboratory of immune response and immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. wenpan@ustc.edu.cn.
  • 11 Hefei National Research Center for Physical Sciences at the Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, China. zhushu@ustc.edu.cn.
  • 12 Key Laboratory of immune response and immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. zhushu@ustc.edu.cn.
  • 13 School of Data Science, University of Science and Technology of China, Hefei, 230026, China. zhushu@ustc.edu.cn.
PMID: 38594251 DOI: 10.1038/s41467-024-47235-2
Abstract

Epithelial barrier dysfunction and crypt destruction are hallmarks of inflammatory bowel disease (IBD). Intestinal stem cells (ISCs) residing in the crypts play a crucial role in the continuous self-renewal and rapid recovery of intestinal epithelial cells (IECs). However, how ISCs are dysregulated in IBD remains poorly understood. Here, we observe reduced DHX9 protein levels in IBD patients, and mice with conditional DHX9 depletion in the intestinal epithelium (Dhx9ΔIEC) exhibit an increased susceptibility to experimental colitis. Notably, Dhx9ΔIEC mice display a significant reduction in the numbers of ISCs and Paneth cells. Further investigation using ISC-specific or Paneth cell-specific Dhx9-deficient mice demonstrates the involvement of ISC-expressed DHX9 in maintaining epithelial homeostasis. Mechanistically, DHX9 deficiency leads to abnormal R-loop accumulation, resulting in genomic instability and the cGAS-STING-mediated inflammatory response, which together impair ISC function and contribute to the pathogenesis of IBD. Collectively, our findings highlight R-loop-mediated genomic instability in ISCs as a risk factor in IBD.

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