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J Allergy Clin Immunol. 2018 Dec;142(6):1793-1807. doi: 10.1016/j.jaci.2017.12.1006. Epub 2018 Mar 2.

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

Author information

1
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. Electronic address: r.stadhouders@erasmusmc.nl.
2
Department of Pulmonary Medicine, Erasmus MC Rotterdam, The Netherlands.
3
Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
4
Institute of Immunology, University Clinics, Ulm, Germany.
5
Center for Biomics, Erasmus MC Rotterdam, The Netherlands.
6
Innate Immunity Unit, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, Paris, France.
7
Department of Pulmonary Medicine, Erasmus MC Rotterdam, The Netherlands. Electronic address: r.hendriks@erasmusmc.nl.

Abstract

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 TH2 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.

KEYWORDS:

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

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