Background

Group 2 innate lymphoid cells (ILC2s) are major producers of cytokines driving allergic asthma and elevated numbers of ILC2s have been detected in blood and sputum of asthma patients. Asthma susceptibility has a strong genetic component, but the underlying mechanisms and whether asthma genetics impact ILC2 biology remains unclear.

Objective

To study the ILC2 transcriptome and epigenome during airway inflammation (AI) in order to couple these to genes and genetic variants associated with asthma pathogenesis.

Methods

Mice harboring a reporter for the key ILC2 transcription factor GATA3 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 employed RNA-Seq, genome-wide identification of histone-3 lysine-4 dimethylation (H3K4me2) marked chromatin and computational approaches to study the ILC2 transcriptome and epigenome.

Results

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. Over 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 Th2 cell - regulatory regions.

Conclusions

ILC2s in AI employ 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 allergic asthma.

中文翻译：

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表观基因组分析将第2组先天性淋巴细胞的基因调控元件与哮喘易感性联系起来

背景

第2组先天性淋巴样细胞（ILC2）是驱动过敏性哮喘的细胞因子的主要产生者，并且在哮喘患者的血液和痰液中检测到ILC2的数量增加。哮喘易感性具有很强的遗传成分，但是尚不清楚其潜在机制以及哮喘遗传学是否影响ILC2生物学。

客观的

研究气道炎症（AI）期间的ILC2转录组和表观基因组，以将其与与哮喘发病相关的基因和遗传变异相结合。

方法

携带关键ILC2转录因子GATA3报告基因的小鼠接受IL-33驱动的AI，并从支气管肺泡灌洗液和纵隔淋巴结中分离出ILC2。人类ILC2s从外周血中纯化并在体外激活。我们采用RNA序列，组蛋白3赖氨酸4甲基化（H3K4me2）标记的染色质的全基因组鉴定和计算方法来研究ILC2转录组和表观基因组。

结果

小鼠中激活的ILC2s表现出一种组织特异性基因表达特征，这种特征是从非常相似的表观基因组中出现的。我们发现了与控制ILC2身份和哮喘相关基因有关的超级增强剂。在全基因组关联研究中发现的300多种与哮喘相关的遗传多态性，定位于ILC2s中的H3K4Me2 ⁺基因调控元件。一组完善的候选因果哮喘相关变体在ILC2（而非Th2细胞）调节区域中独特富集。

结论

AI中的ILC2使用灵活的表观基因组，将其适应性与具有功能可塑性的新微环境相结合。重要的是，我们揭示了ILC2s的基因调控机制与哮喘的遗传基础之间的密切相关性，支持了ILC2s在过敏性哮喘中的致病作用。