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11q13.5处的远端增强因子促进Treg细胞抑制结肠炎
作者:小柯机器人 发布时间:2020/5/15 15:10:22

英国巴伯拉罕研究所Rahul Roychoudhuri和Charlotte J. Imianowski研究小组在研究中取得进展。他们发现位于风险基因座11 q13.5处的远端增强子促进T reg细胞抑制结肠炎。 这一研究成果在线发表在2020年5月13日的《自然》上。

使用共有、同义性来指导小鼠中人类同源增强子功能丧失分析,研究人员发现在染色体11q13.5处存在自身免疫病和过敏性疾病的风险位点,其包含一个远端在CD4 +调节性T(Treg)细胞中起作用的增强子,并且该增强子是Treg介导的结肠炎抑制所必需的。增强子招募转录因子STAT5和NF-κB来调控信号驱动的Lrrc32表达,Lrrc32编码糖蛋白A为主的重复序列(GARP)。

Lrrc32基因缺失导致小鼠早期致死性,而缺乏增强子的小鼠却可以存活,但在Foxp3 + Treg细胞中缺乏GARP的表达,则导致在疾病细胞转移模型中无法控制结肠炎。在人类Treg细胞中增强子与LRRC32的启动子形成构象相互作用,并且增强子风险变异体与组蛋白乙酰化和GARP表达降低有关。

最后,使用CRISPR激活(CRISPRa)工具对11q13.5进行功能精细映射,可以在诱导GARP表达的风险变体rs11236797附近识别CRISPRa的响应元件。这些发现为解释与11q13.5风险位点相关的免疫疾病提供了机制基础,并揭示了GARP可作为其治疗的潜在靶点。

据悉,复杂自身免疫病和过敏性疾病的易感遗传变异集中在名为增强子的非编码调控元件内。大多数与疾病相关的增强子功能尚不清楚,部分原因是这些增强子与其调控基因之间的距离、对它们所处细胞类型了解不足以及无法在体外概括免疫疾病的生物学特性。

附:英文原文

Title: A distal enhancer at risk locus 11q13.5 promotes suppression of colitis by T reg cells

Author: Rabab Nasrallah, Charlotte J. Imianowski, Lara Bossini-Castillo, Francis M. Grant, Mikail Dogan, Lindsey Placek, Lina Kozhaya, Paula Kuo, Firas Sadiyah, Sarah K. Whiteside, Maxwell R. Mumbach, Dafni Glinos, Panagiota Vardaka, Carly E. Whyte, Teresa Lozano, Toshitsugu Fujita, Hodaka Fujii, Adrian Liston, Simon Andrews, Adeline Cozzani, Jie Yang, Suman Mitra, Enrico Lugli, Howard Y. Chang, Derya Unutmaz, Gosia Trynka, Rahul Roychoudhuri

Issue&Volume: 2020-05-13

Abstract: Genetic variations underlying susceptibility to complex autoimmune and allergic diseases are concentrated within noncoding regulatory elements termed enhancers1. The functions of a large majority of disease-associated enhancers are unknown, in part owing to their distance from the genes they regulate, a lack of understanding of the cell types in which they operate, and our inability to recapitulate the biology of immune diseases in vitro. Here, using shared synteny to guide loss-of-function analysis of homologues of human enhancers in mice, we show that the prominent autoimmune and allergic disease risk locus at chromosome 11q13.52,3,4,5,6,7 contains a distal enhancer that is functional in CD4+ regulatory T (Treg) cells and required for Treg-mediated suppression of colitis. The enhancer recruits the transcription factors STAT5 and NF-κB to mediate signal-driven expression of Lrrc32, which encodes the protein glycoprotein A repetitions predominant (GARP). Whereas disruption of the Lrrc32 gene results in early lethality, mice lacking the enhancer are viable but lack GARP expression in Foxp3+ Treg cells, which are unable to control colitis in a cell-transfer model of the disease. In human Treg cells, the enhancer forms conformational interactions with the promoter of LRRC32 and enhancer risk variants are associated with reduced histone acetylation and GARP expression. Finally, functional fine-mapping of 11q13.5 using CRISPR-activation (CRISPRa) identifies a CRISPRa-responsive element in the vicinity of risk variant rs11236797 capable of driving GARP expression. These findings provide a mechanistic basis for association of the 11q13.5 risk locus with immune-mediated diseases and identify GARP as a potential target in their therapy.

DOI: 10.1038/s41586-020-2296-7

Source: https://www.nature.com/articles/s41586-020-2296-7

期刊信息

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