DOI | 10.1038/s41586-019-1844-5
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| Somatic inflammatory gene mutations in human ulcerative colitis epithelium |
| Nanki, Kosaku1,2; Fujii, Masayuki1,3; Shimokawa, Mariko1; Matano, Mami1; Nishikori, Shingo1,4; Date, Shoichi1,4; Takano, Ai1; Toshimitsu, Kohta1,2; Ohta, Yuki1; Takahashi, Sirirat1; Sugimoto, Shinya1,2; Ishimaru, Kazuhiro1,3; Kawasaki, Kenta1,2; Nagai, Yoko4; Ishii, Ryota5; Yoshida, Kosuke1,2; Sasaki, Nobuo1,2; Hibi, Toshifumi2,6; Ishihara, Soichiro3; Kanai, Takanori2; Sato, Toshiro1,2
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| 2020-05-01
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发表期刊 | NATURE
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ISSN | 0028-0836
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EISSN | 1476-4687
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出版年 | 2020
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卷号 | 577期号:7789页码:254-+ |
文章类型 | Article
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语种 | 英语
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国家 | Japan |
英文关键词 | With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations(1-7). 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 proapoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice(8-11), 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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领域 | 地球科学
; 气候变化
; 资源环境
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收录类别 | SCI-E
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WOS记录号 | WOS:000506682500044
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WOS关键词 | POLYMERIC IMMUNOGLOBULIN RECEPTOR
; NITRIC-OXIDE SYNTHASE
; CLONAL HEMATOPOIESIS
; SECRETORY COMPONENT
; COLONIC-MUCOSA
; CELLS
; INTERLEUKIN-17
; EXPRESSION
; CANCER
; SELECTION
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WOS类目 | Multidisciplinary Sciences
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WOS研究方向 | Science & Technology - Other Topics
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引用统计 |
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文献类型 | 期刊论文
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条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/281471
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专题 | 地球科学 资源环境科学 气候变化
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作者单位 | 1.Keio Univ, Dept Organoid Med, Sch Med, Tokyo, Japan; 2.Keio Univ, Dept Gastroenterol, Sch Med, Tokyo, Japan; 3.Univ Tokyo, Dept Surg Oncol, Tokyo, Japan; 4.Otsuka Pharmaceut Co Ltd, Fujii Mem Res Inst, Shiga, Japan; 5.Keio Univ Hosp, Biostat Unit, Clin & Translat Res Ctr, Tokyo, Japan; 6.Kitasato Inst Hosp, Ctr Adv IBD Res & Treatment, Tokyo, Japan
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推荐引用方式 GB/T 7714 |
Nanki, Kosaku,Fujii, Masayuki,Shimokawa, Mariko,et al. Somatic inflammatory gene mutations in human ulcerative colitis epithelium[J].
NATURE,2020,577(7789):254-+.
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APA |
Nanki, Kosaku.,Fujii, Masayuki.,Shimokawa, Mariko.,Matano, Mami.,Nishikori, Shingo.,...&Sato, Toshiro.(2020).Somatic inflammatory gene mutations in human ulcerative colitis epithelium.NATURE,577(7789),254-+.
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MLA |
Nanki, Kosaku,et al."Somatic inflammatory gene mutations in human ulcerative colitis epithelium".NATURE 577.7789(2020):254-+.
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