A super enhancer controls expression and chromatin architecture within the MHC class II locus.

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Parimal Majumder, Joshua T Lee, Andrew R Rahmberg, Gaurav Kumar, Tian Mi, Christopher D Scharer, Jeremy M Boss
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引用次数: 18

Abstract

Super enhancers (SEs) play critical roles in cell type-specific gene regulation. The mechanisms by which such elements work are largely unknown. Two SEs termed DR/DQ-SE and XL9-SE are situated within the human MHC class II locus between the HLA-DRB1 and HLA-DQA1 genes and are highly enriched for disease-causing SNPs. To test the function of these elements, we used CRISPR/Cas9 to generate a series of mutants that deleted the SE. Deletion of DR/DQ-SE resulted in reduced expression of HLA-DRB1 and HLA-DQA1 genes. The SEs were found to interact with each other and the promoters of HLA-DRB1 and HLA-DQA1. DR/DQ-SE also interacted with neighboring CTCF binding sites. Importantly, deletion of DR/DQ-SE reduced the local chromatin interactions, implying that it functions as the organizer for the local three-dimensional architecture. These data provide direct mechanisms by which an MHC-II SE contributes to expression of the locus and suggest how variation in these SEs may contribute to human disease and altered immunity.

一个超级增强子控制着 MHC II 类基因座内的表达和染色质结构。
超级增强子(SE)在细胞类型特异性基因调控中发挥着关键作用。这类元件的作用机制在很大程度上还不为人所知。被称为 DR/DQ-SE 和 XL9-SE 的两个 SE 位于人类 MHC II 类基因座中的 HLA-DRB1 和 HLA-DQA1 基因之间,并且高度富集了致病 SNPs。为了测试这些元件的功能,我们使用 CRISPR/Cas9 生成了一系列删除 SE 的突变体。DR/DQ-SE的缺失导致HLA-DRB1和HLA-DQA1基因的表达减少。研究发现 SE 与 HLA-DRB1 和 HLA-DQA1 的启动子相互作用。DR/DQ-SE 还与邻近的 CTCF 结合位点相互作用。重要的是,DR/DQ-SE的缺失减少了局部染色质的相互作用,这意味着它起到了局部三维结构组织者的作用。这些数据提供了 MHC-II SE 促进基因座表达的直接机制,并提示了这些 SE 的变异可能如何导致人类疾病和免疫力的改变。
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来源期刊
Molecular Neurobiology
Molecular Neurobiology 医学-神经科学
CiteScore
9.00
自引率
2.00%
发文量
480
审稿时长
1 months
期刊介绍: Molecular Neurobiology is an exciting journal for neuroscientists needing to stay in close touch with progress at the forefront of molecular brain research today. It is an especially important periodical for graduate students and "postdocs," specifically designed to synthesize and critically assess research trends for all neuroscientists hoping to stay active at the cutting edge of this dramatically developing area. This journal has proven to be crucial in departmental libraries, serving as essential reading for every committed neuroscientist who is striving to keep abreast of all rapid developments in a forefront field. Most recent significant advances in experimental and clinical neuroscience have been occurring at the molecular level. Until now, there has been no journal devoted to looking closely at this fragmented literature in a critical, coherent fashion. Each submission is thoroughly analyzed by scientists and clinicians internationally renowned for their special competence in the areas treated.
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