Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes  Stephanie Brand, PhD, René Teich,

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Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes  Stephanie Brand, PhD, René Teich, PhD, Tanja Dicke, PhD, Hani Harb, BSc, Ali Ö. Yildirim, MD, Jörg Tost, PhD, Regine Schneider- Stock, PhD, Robert A. Waterland, PhD, Uta-Maria Bauer, PhD, Erika von Mutius, MD, MSc, Holger Garn, PhD, Petra I. Pfefferle, PhD, DrPH, Harald Renz, MD  Journal of Allergy and Clinical Immunology  Volume 128, Issue 3, Pages 618-625.e7 (September 2011) DOI: 10.1016/j.jaci.2011.04.035 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 TH1/TH2 cytokine balance after prenatal A lwoffii F78 exposure. A, Concentrations of IFN-γ, IL-4, IL-5, IL-13, and IL-10 in the supernatant of anti-CD3/anti-CD28–stimulated mononuclear spleen cells from offspring from A lwoffii F78– or sham-exposed (PBS) mothers. B, Relative mRNA expression of IFN-γ, IL-4, IL-5, IL-13, and IL-10 in CD4+CD25− splenic T cells. Data represent the results of 2 independent experiments, each with 4 to 8 individually analyzed animals per group. ∗P < .05, ∗∗P < .01. Journal of Allergy and Clinical Immunology 2011 128, 618-625.e7DOI: (10.1016/j.jaci.2011.04.035) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Effects of anti−IFN-γ treatment during OVA challenge in offspring of A lwoffii F78−exposed mothers. A, Differential leukocyte numbers in BAL fluids. B, Quantification of inflammation and mucus-producing goblet cells. C, Airway responsiveness to methacholine (MCH) in offspring. D, In vitro TH2 cytokine production by restimulated mononuclear splenocytes. E, OVA-specific serum antibody levels (n = 8 mice per group). ns, Not significant. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2011 128, 618-625.e7DOI: (10.1016/j.jaci.2011.04.035) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 H4 acetylation within the IFNG and IL4 promoters after prenatal A lwoffii F78 exposure. H4ac and H3K27me3 levels within the IFNG, IL4, and IL5 promoters and the CNS1 region were determined by means of ChIP in CD4+CD25− T cells purified from spleens of offspring from A lwoffii F78– or sham-exposed (PBS) mothers. Data represent the results of 2 independent experiments, each with 4 to 8 individually analyzed animals per group. ns, Not significant. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2011 128, 618-625.e7DOI: (10.1016/j.jaci.2011.04.035) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effects of garcinol treatment during OVA challenge on H4 acetylation at the IFNG promoter of CD4+CD25− splenic T cells and asthma protection by prenatal A lwoffii F78 exposure. A, H4ac within the IFNG and IL4 promoters and CNS1 (for control groups, see Fig E4). B, Differential leukocyte numbers in BAL fluid. C, Quantification of airway inflammation and mucus-producing goblet cells. D, Airway responsiveness to aerosolized methacholine (MCH). E, In vitro cytokine production by restimulated splenocytes. Gar, Garcinol. Data represent the results of 2 independent experiments, each with 4 to 8 individually analyzed animals per group. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2011 128, 618-625.e7DOI: (10.1016/j.jaci.2011.04.035) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 H4 acetylation within the STAT-4 promoter after prenatal A lwoffii F78 exposure. H4ac and H3K27me3 levels within the STAT-4 promoter were determined by means of ChIP in CD4+ CD25+ T cells purified from spleens of offspring from A lwoffii F78- or sham-exposed (PBS) mothers. Data represent the results of 2 independent experiments, each with 4 to 8 individually analyzed animals per group. ns, Not significant. Journal of Allergy and Clinical Immunology 2011 128, 618-625.e7DOI: (10.1016/j.jaci.2011.04.035) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Modulation of DNA methylation within CNS1 in splenic CD4+CD25− T cells from offspring after prenatal A lwoffii F78 exposure. Positions of CpG sites correspond to their positions upstream of the transcription start site of annotated sequence NM_008337 for IFNG (A), NM_010558 (IL5), and NM_021283 (IL4) for IL4 and CNS1 (B). Data represent results of 2 independent experiments, each with 4 to 8 individually analyzed animals per group. ∗P < .05, ∗∗P < .01. Journal of Allergy and Clinical Immunology 2011 128, 618-625.e7DOI: (10.1016/j.jaci.2011.04.035) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 T-cell activation and proliferation after garcinol treatment. A, Ex vivo proliferation of splenic T cells of garcinol- and PBS-treated mice determined by means of CD4+ and CFSE labeling and subsequent FACS analysis. B, In vivo proliferation of splenic CFSE-labeled CD4+ T cells transferred from garcinol- or PBS-treated mice intravenously into BALB/cscid mice determined at day 8 by means of FACS analysis. Data are from 1 representative mouse per group. Two independent experiments were performed, each with 2 to 4 individually analyzed animals per group. Journal of Allergy and Clinical Immunology 2011 128, 618-625.e7DOI: (10.1016/j.jaci.2011.04.035) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Modulation of H4 acetylation at the IFNG promoter by using the histone acetyltransferase inhibitor garcinol (control groups). H4ac levels within the IFNG and IL4 promoter and CNS1 in CD4+CD25− splenic T cells from offspring treated with garcinol before each OVA challenge were analyzed by means of ChIP. Data represent the results of 2 independent experiments, each with 4 to 8 individually analyzed animals per group. ns, Not significant. Respective data of experimental groups are provided in Fig 4. ns, Not significant. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2011 128, 618-625.e7DOI: (10.1016/j.jaci.2011.04.035) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions