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