11q13.5處的遠端增強因子促進Treg細胞抑制結腸炎
作者：
小柯機器人發布時間：2020/5/15 15:10:22
英國巴伯拉罕研究所Rahul Roychoudhuri和Charlotte J. Imianowski研究小組在研究中取得進展。他們發現位於風險基因座11 q13.5處的遠端增強子促進T reg細胞抑制結腸炎。 這一研究成果在線發表在2020年5月13日的《自然》上。
使用共有、同義性來指導小鼠中人類同源增強子功能喪失分析，研究人員發現在染色體11q13.5處存在自身免疫病和過敏性疾病的風險位點，其包含一個遠端在CD4 +調節性T（Treg）細胞中起作用的增強子，並且該增強子是Treg介導的結腸炎抑制所必需的。增強子招募轉錄因子STAT5和NF-κB來調控信號驅動的Lrrc32表達，Lrrc32編碼糖蛋白A為主的重複序列（GARP）。
Lrrc32基因缺失導致小鼠早期致死性，而缺乏增強子的小鼠卻可以存活，但在Foxp3 + Treg細胞中缺乏GARP的表達，則導致在疾病細胞轉移模型中無法控制結腸炎。在人類Treg細胞中增強子與LRRC32的啟動子形成構象相互作用，並且增強子風險變異體與組蛋白乙醯化和GARP表達降低有關。
最後，使用CRISPR激活（CRISPRa）工具對11q13.5進行功能精細映射，可以在誘導GARP表達的風險變體rs11236797附近識別CRISPRa的響應元件。這些發現為解釋與11q13.5風險位點相關的免疫疾病提供了機制基礎，並揭示了GARP可作為其治療的潛在靶點。
據悉，複雜自身免疫病和過敏性疾病的易感遺傳變異集中在名為增強子的非編碼調控元件內。大多數與疾病相關的增強子功能尚不清楚，部分原因是這些增強子與其調控基因之間的距離、對它們所處細胞類型了解不足以及無法在體外概括免疫疾病的生物學特性。
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