小柯机器人

研究发现溃疡性结肠炎上皮细胞的炎症基因突变
2019-12-19 13:50

日本庆应义塾大学医学院Toshiro Sato课题组的近期研究揭示了人溃疡性结肠炎上皮中的体细胞炎症基因突变。相关论文于2019年12月18日在线发表在《自然》杂志上。

研究人员使用来自76个人类结肠类器官体克隆的全外显子组测序数据,确定了溃疡性结肠炎患者发炎上皮细胞中的一种独特的体细胞突变模式。受影响的上皮细胞在与IL-17信号相关的多个基因中积累了体细胞突变,包括NFKBIZ、ZC3H12A和PIGR,这些基因在结肠癌中很少受到影响。靶向测序验证了与IL-17信号传导有关突变的普遍扩散。

在结肠类器官中的CRISPR无偏倚敲除筛选显示,这些突变赋予对IL-17A诱导的促凋亡反应的抗性。这些基因突变中的一些已知会加剧小鼠实验性结肠炎,并且人结肠上皮细胞的体细胞突变可能与炎症过程存在因果关联。这些发现凸显了适应不利微环境的遗传改变,并证明了其对溃疡性结肠炎发病机理的潜在影响。

据介绍,随着年龄的增长,正常人体组织会出现携带癌症突变体细胞克隆的扩增。但是,在非肿瘤性肠中是否存在这样的克隆扩增仍是未知的。

附:英文原文

Title: Somatic inflammatory gene mutations in human ulcerative colitis epithelium

Author: 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

Issue&Volume: 2019-12-18

Abstract: With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1,2,3,4,5,6,7. 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 mice8,9,10,11, 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.

DOI: 10.1038/s41586-019-1844-5

Source: https://www.nature.com/articles/s41586-019-1844-5

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0