Epigenome analysis links gene regulatory elements in group 2 innate lymphocytes to asthma susceptibility - 06/12/18
, Bobby W.S. Li, MSc a, Marjolein J.W. de Bruijn, BSc a, Antonio Gomez, PhD b, c, Tata Nageswara Rao, PhD d, ∗, Hans Jörg Fehling, PhD d, Wilfred F.J. van IJcken, PhD e, Ai Ing Lim, PhD f, g, James P. Di Santo, MD, PhD f, g, Thomas Graf, PhD b, c, Rudi W. Hendriks, PhD a, ⁎ 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 numéro
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