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Somatic inflammatory gene mutations in human ulcerative colitis epithelium 期刊论文
NATURE, 2020, 577 (7789) : 254-+
作者:  Nanki, Kosaku;  Fujii, Masayuki;  Shimokawa, Mariko;  Matano, Mami;  Nishikori, Shingo;  Date, Shoichi;  Takano, Ai;  Toshimitsu, Kohta;  Ohta, Yuki;  Takahashi, Sirirat;  Sugimoto, Shinya;  Ishimaru, Kazuhiro;  Kawasaki, Kenta;  Nagai, Yoko;  Ishii, Ryota;  Yoshida, Kosuke;  Sasaki, Nobuo;  Hibi, Toshifumi;  Ishihara, Soichiro;  Kanai, Takanori;  Sato, Toshiro
收藏  |  浏览/下载:27/0  |  提交时间:2020/07/03

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.


  
Recycled ancient ghost carbonate in the Pitcairn mantle plume 期刊论文
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (35) : 8682-8687
作者:  Wang, Xiao-Jun;  Chen, Li-Hui;  Hofmann, Albrecht W.;  Hanyu, Takeshi;  Kawabata, Hiroshi;  Zhong, Yuan;  Xie, Lie-Wen;  Shi, Jin-Hua;  Miyazaki, Takashi;  Hirahara, Yuka;  Takahashi, Toshiro;  Senda, Ryoko;  Chang, Qing;  Vaglarov, Bogdan S.;  Kimura, Jun-Ichi
收藏  |  浏览/下载:18/0  |  提交时间:2019/11/27
Pitcairn mantle plume  EM1  magnesium isotopes  ancient carbonate-bearing sediments