Department of Pulmonary Medicine, Erasmus MC Rotterdam, The Netherlands; Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
Department of Pulmonary Medicine, Erasmus MC Rotterdam, The Netherlands.
J Allergy Clin Immunol. 2018 Dec;142(6):1793-1807. doi: 10.1016/j.jaci.2017.12.1006. Epub 2018 Mar 2.
Group 2 innate lymphoid cells (ILC2s) are major producers of the cytokines driving allergic asthma, and increased ILC2 numbers have been detected in blood and sputum of asthmatic patients. Asthma susceptibility has a strong genetic component, but the underlying mechanisms and whether asthma genetics affect ILC2 biology remain unclear.
We sought to study the ILC2 transcriptome and epigenome during airway inflammation (AI) to couple these to genes and genetic variants associated with asthma pathogenesis.
Mice harboring a reporter for the key ILC2 transcription factor GATA-3 were subjected to IL-33-driven AI, and ILC2s were isolated from bronchoalveolar lavage fluid and mediastinal lymph nodes. Human ILC2s were purified from peripheral blood and activated in vitro. We used RNA sequencing, genome-wide identification of histone-3 lysine-4 dimethylation-marked chromatin, and computational approaches to study the ILC2 transcriptome and epigenome.
Activated ILC2s in mice displayed a tissue-specific gene expression signature that emerged from remarkably similar epigenomes. We identified superenhancers implicated in controlling ILC2 identity and asthma-associated genes. More than 300 asthma-associated genetic polymorphisms identified in genome-wide association studies localized to H3K4Me2 gene regulatory elements in ILC2s. A refined set of candidate causal asthma-associated variants was uniquely enriched in ILC2, but not T2 cell, regulatory regions.
ILC2s in AI use a flexible epigenome that couples adaptation to new microenvironments with functional plasticity. Importantly, we reveal strong correlations between gene regulatory mechanisms in ILC2s and the genetic basis of asthma, supporting a pathogenic role for ILC2s in patients with allergic asthma.
2 型固有淋巴细胞（ILC2）是驱动过敏性哮喘的细胞因子的主要产生者，在哮喘患者的血液和痰液中已检测到 ILC2 数量增加。哮喘易感性具有很强的遗传成分，但潜在机制以及哮喘遗传学是否影响 ILC2 生物学仍不清楚。
我们试图研究气道炎症（AI）期间 ILC2 的转录组和表观基因组，将这些与与哮喘发病机制相关的基因和遗传变异相关联。
携带关键 ILC2 转录因子 GATA-3 报告基因的小鼠接受 IL-33 驱动的 AI，从支气管肺泡灌洗液和纵隔淋巴结中分离 ILC2。从外周血中纯化人 ILC2 并在体外激活。我们使用 RNA 测序、组蛋白-3 赖氨酸-4 二甲基化标记染色质的全基因组鉴定以及计算方法研究 ILC2 的转录组和表观基因组。
激活的小鼠 ILC2 显示出一种组织特异性的基因表达特征，这种特征来自于非常相似的表观基因组。我们确定了超级增强子，这些超级增强子参与控制 ILC2 身份和与哮喘相关的基因。全基因组关联研究中确定的 300 多个哮喘相关遗传多态性定位于 ILC2 中的 H3K4Me2 基因调控元件。一组经过改进的候选因果哮喘相关变体在 ILC2 中但不在 T2 细胞调节区域中是唯一富集的。
AI 中的 ILC2 使用灵活的表观基因组，将适应新的微环境与功能可塑性相结合。重要的是，我们揭示了 ILC2 中的基因调控机制与哮喘遗传基础之间的强烈相关性，支持 ILC2 在过敏性哮喘患者中的致病作用。
