Epigenome analysis links gene regulatory elements in group 2 innate lymphocytes to asthma susceptibility - 06/12/18
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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Group 2 innate lymphoid cell, epigenetics, epigenome, asthma, airway inflammation, genome-wide association study, superenhancer, transcription factor, TH2 cell, GATA-3
Abbreviations used : AI, aILC2, BAL, GFI1, GRE, GWAS, HDM, H3K4me2, ICOS, ILC, ILC2, IL-33R, KLRG1, MLN, nILC2, RNA-Seq, SE, SNP, TF
Plan
R.S. was supported by an EMBO Long-term Fellowship (ALTF 1201-2014), a Marie Curie Individual Fellowship (H2020-MSCA-IF-2014), and an NWO Veni Fellowship (grant no. 91617114). B.W.S.L. was supported by the Lung Foundation Netherlands (3.2.12.067). T.G. was supported by a European Research Council (ERC) Synergy Grant (4DGenome). A.I.L. is a scholar in the Pasteur-Paris University (PPU) International PhD program and supported by a PhD International Training Network grant from European Union’s 7th Framework Programme under grant agreement n°317057 (HOMIN). J.P.D.S. received grant support from the Institut Pasteur and Inserm. |
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Disclosure of potential conflict of interest: R. Stadhouders has received grants from The Netherlands Organization for Scientific Research (VENI 91617114), the European Molecular Biology Organization (ALTF 1201-2014), and the European Commission (H2020-MSCA-IF-2014). H. J. Fehling has received a grant from Deutsche Forschungsgemeinschaft (FE 578/3-1). A. I. Lim has received a grant from the PhD International Training Network (FP7 no. 317057; HOMIN). J. P. Di Santo has received grants from Institut Pasteur and Institut national de la santé et de la recherche médicale. T. Graf has received grant support from a European Research Council Synergy Grant (4D-Genome). R. W. Hendriks has received a grant from Lung Foundation Netherlands (3.2.12.067). The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 6
P. 1793-1807 - décembre 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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