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Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes

2011; Elsevier BV; Volume: 128; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2011.04.035

1097-6825

Stéphanie Brand, René Teich, Tanja Dicke, Hani Harb, Ali Önder Yildirim, Jörg Tost, Regine Schneider‐Stock, Robert A. Waterland, Uta‐Maria Bauer, Erika von Mutius, Holger Garn, Petra Ina Pfefferle, Harald Renz,

Asthma and respiratory diseases

BackgroundBronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important mechanism by which environmental factors might interact with genes involved in allergy and asthma development.ObjectiveThis study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure.MethodsPregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in TH1- and TH2-relevant genes of CD4+ T cells.ResultsPrenatal administration of A lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-γ dependent. Furthermore, the IFNG promoter of CD4+ T cells in the offspring revealed a significant protection against loss of histone 4 (H4) acetylation, which was closely associated with IFN-γ expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma-protective phenotype. Regarding TH2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic TH2 regulatory region conserved noncoding sequence 1 (CNS1).ConclusionThese data support the hygiene concept and indicate that microbes operate by means of epigenetic mechanisms. This provides a new mechanism in the understanding of gene-environment interactions in the context of allergy protection. Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important mechanism by which environmental factors might interact with genes involved in allergy and asthma development. This study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure. Pregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in TH1- and TH2-relevant genes of CD4+ T cells. Prenatal administration of A lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-γ dependent. Furthermore, the IFNG promoter of CD4+ T cells in the offspring revealed a significant protection against loss of histone 4 (H4) acetylation, which was closely associated with IFN-γ expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma-protective phenotype. Regarding TH2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic TH2 regulatory region conserved noncoding sequence 1 (CNS1). These data support the hygiene concept and indicate that microbes operate by means of epigenetic mechanisms. This provides a new mechanism in the understanding of gene-environment interactions in the context of allergy protection.