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

Xingxing Ren, Qiuyuan Liu, Peirong Zhou, Tingyue Zhou, Decai Wang, Qiao Mei, Richard A. Flavell, Zhanju Liu (), Mingsong Li (), Wen Pan () and Shu Zhu ()
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Xingxing Ren: University of Science and Technology of China
Qiuyuan Liu: The First Affiliated Hospital of Anhui Medical University
Peirong Zhou: Third Affiliated Hospital of Guangzhou Medical University
Tingyue Zhou: University of Science and Technology of China
Decai Wang: University of Science and Technology of China
Qiao Mei: The First Affiliated Hospital of Anhui Medical University
Richard A. Flavell: Yale University School of Medicine
Zhanju Liu: Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine
Mingsong Li: Third Affiliated Hospital of Guangzhou Medical University
Wen Pan: University of Science and Technology of China
Shu Zhu: University of Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47235-2

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