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Merck
  • Somatic inflammatory gene mutations in human ulcerative colitis epithelium.

Somatic inflammatory gene mutations in human ulcerative colitis epithelium.

Nature (2019-12-20)
Kosaku Nanki, Masayuki Fujii, Mariko Shimokawa, Mami Matano, Shingo Nishikori, Shoichi Date, Ai Takano, Kohta Toshimitsu, Yuki Ohta, Sirirat Takahashi, Shinya Sugimoto, Kazuhiro Ishimaru, Kenta Kawasaki, Yoko Nagai, Ryota Ishii, Kosuke Yoshida, Nobuo Sasaki, Toshifumi Hibi, Soichiro Ishihara, Takanori Kanai, Toshiro Sato
초록

With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1-7. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling-including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice8-11, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.

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Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
Anti-PIGR antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution, Ab2