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Author Spotlight: Studying the Epithelial Effects of Intestinal Inflammation In Vitro on Established Murine Colonoids
Published on: June 2, 2023
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Somatic inflammatory gene mutations in human ulcerative colitis epithelium
Kosaku Nanki1,2, Masayuki Fujii1,3, Mariko Shimokawa1
1Department of Organoid Medicine, Keio University School of Medicine, Tokyo, Japan.
Nature
|December 20, 2019
Summary
Aging tissues accumulate cancer mutations. In ulcerative colitis patients, colon cells develop mutations in IL-17 signaling genes, potentially driving inflammation and disease.
Area of Science:
- Gastroenterology
- Genetics
- Immunology
Background:
- Aging tissues accumulate somatic clones with cancer mutations.
- Clonal expansion in non-neoplastic human intestine is not well understood.
- Ulcerative colitis involves chronic intestinal inflammation.
Purpose of the Study:
- Investigate somatic mutagenesis in the colon epithelium of ulcerative colitis patients.
- Determine if mutations in the inflamed colon confer functional advantages.
- Explore the link between somatic mutations and ulcerative colitis pathogenesis.
Main Methods:
- Whole-exome sequencing of 76 human colon organoids.
- Targeted sequencing to validate mutation spread.
- CRISPR-based knockout screening in colon organoids.
Main Results:
- Identified a unique pattern of somatic mutations in ulcerative colitis colon epithelium.
- Mutations were found in IL-17 signaling pathway genes (NFKBIZ, ZC3H12A, PIGR).
- Mutations conferred resistance to IL-17A-induced apoptosis in colon organoids.
Conclusions:
- Somatic mutagenesis in human colon epithelium is linked to inflammation.
- Mutations may promote survival in the hostile microenvironment of ulcerative colitis.
- This genetic adaptation could contribute to ulcerative colitis pathogenesis.
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