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

Publication date: Available online 2 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Ralph Stadhouders, Bobby W.S. Li, Marjolein J.W. de Bruijn, Antonio Gomez, Tata Nageswara Rao, Hans Jörg Fehling, Wilfred F.J. van IJcken, Ai Ing Lim, James P. Di Santo, Thomas Graf, Rudi W. Hendriks
BackgroundGroup 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.ObjectiveTo study the ILC2 transcriptome and epigenome during airway inflammation (AI) in order to couple these to genes and genetic variants associated with asthma pathogenesis.MethodsMice 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.ResultsActivated 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.ConclusionsILC2s 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.

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