Epigenome analysis links gene regulatory elements in group 2 innate lymphocytes to asthma susceptibility

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:142

Article

Stadhouders, Ralph^1,3,4  Li, Bobby W. S.¹  de Bruijn, Marjolein J. W.¹  Gomez, Antonio^3,4  Nageswara, Tata^5,8  Fehling, Hans Joerg⁵  van IJcken, Wilfred F. J.²  Lim, Ai Ing^6,7  Di Santo, James P.^6,7  Graf, Thomas^3,4  Hendriks, Rudi W.¹ 

[1] Erasmus MC, Dept Pulm Med, Room Ee2251a, NL-3000 CA Rotterdam, Netherlands

[2] Erasmus MC, Ctr Biom, Rotterdam, Netherlands

[3] BIST, CRG, Barcelona, Spain

[4] Univ Pompeu Fabra, Barcelona, Spain

[5] Univ Clin, Inst Immunol, Ulm, Germany

[6] Inst Pasteur, Innate Immun Unit, Paris, France

[7] INSERM, U1223, Paris, France

[8] Univ Hosp Basel, Dept Biomed, Expt Hematol, Basel, Switzerland

关键词: Group 2 innate lymphoid cell;    epigenetics;    epigenome;    asthma;    airway inflammation;    genome-wide association study;    superenhancer;    transcription factor;    T(H)2 cell;    GATA-3;   

DOI  :  10.1016/j.jaci.2017.12.1006

来源: Elsevier

【 摘 要 】

Background: 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. Objective: 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. Methods: 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. 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. 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 T(H)2 cell, regulatory regions. Conclusions: 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.

【 授权许可】

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