Vitamin D receptor binds to the ε germline gene promoter and exhibits transrepressive activity Milena Milovanovic, MD, Guido Heine, MD, Werner Hallatschek,

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Vitamin D receptor binds to the ε germline gene promoter and exhibits transrepressive activity Milena Milovanovic, MD, Guido Heine, MD, Werner Hallatschek, PhD, Bastian Opitz, MD, Andreas Radbruch, PhD, Margitta Worm, MD Journal of Allergy and Clinical Immunology Volume 126, Issue 5, Pages 1016-1023.e4 (November 2010) DOI: 10.1016/j.jaci.2010.08.020 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Calcitriol inhibits εGLT expression in CD23+ B cells. A, CD23+ and CD23− cell subsets were purified after 48 hours of anti-CD40/IL-4 stimulation. VDR mRNA expression was analyzed by means of RT-PCR (n = 5). ∗P < .05. B and C, B cells were stimulated with anti-CD40/IL-4 with or without calcitriol for 48 hours. After purification of CD23+ cells, cyp24 and εGLT expression was determined by means of RT-PCR (n = 6). Journal of Allergy and Clinical Immunology 2010 126, 1016-1023.e4DOI: (10.1016/j.jaci.2010.08.020) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 The VDR/RXRα heterodimer binds to the Iε region. A, Schematic diagram of Iε. B and C, CD23+ B cells treated with anti-CD40/IL-4 with or without calcitriol were used for VDR or RXRα ChIP. Iε, trpv6, and orf regions were amplified by using qRT-PCR. Data are shown as the relative amount of antibody bound to unprecipitated DNA as means ± SEMs (n = 6). ∗P < .05. Journal of Allergy and Clinical Immunology 2010 126, 1016-1023.e4DOI: (10.1016/j.jaci.2010.08.020) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 VDR complex in the Iε region. CD23+ B cells were stimulated with calcitriol for the time indicated, and SMRT (A), HDAC1 (B), and HDAC3 (C) ChIP was performed. Iε was analyzed by means of qRT-PCR. Data are shown as the relative amount of antibody bound to unprecipitated DNA as means ± SEMs (n = 3-6). ∗P < .05. n.d., Not detectable. Journal of Allergy and Clinical Immunology 2010 126, 1016-1023.e4DOI: (10.1016/j.jaci.2010.08.020) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Calcitriol-induced Iε deacetylation regulates εGT. A and B, CD23+ cells underwent AcH3 or AcH4 ChIP, followed by gene amplification (n = 6). C and D, CD23+ cells stimulated with or without calcitriol, apicidin, MS-275, or As2O3 underwent AcH3 or AcH4 ChIP, followed by Iε amplification (n = 4). E, εGLT was analyzed in B cells stimulated with CD40/IL-4 with or without calcitriol, MS-275, apicidin, or As2O3 (n = 5). ∗P < .05. Journal of Allergy and Clinical Immunology 2010 126, 1016-1023.e4DOI: (10.1016/j.jaci.2010.08.020) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Functional analysis of VDREs in the Iε region. HEK-239 cells were transfected with SV40-pGL3-luciferase, CYP27B1-SV40-pGL3-luciferase, VDREs-Iε-SV40-pGLT-luciferase, or VDREs-SV40-pGLT-luciferase. Cells were cotransfected with VDR and Renilla expression vector. On calcitriol stimulation, the luciferase activity was measured and normalized to the activity of the Renilla expression vector. Data are shown as means ± SEMs from 5 independent experiments. ∗P < .05. Journal of Allergy and Clinical Immunology 2010 126, 1016-1023.e4DOI: (10.1016/j.jaci.2010.08.020) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Model demonstrating the role of acetylation in εGT. A, In resting B cells deacetylated histones are surrounding the Iε region, and the chromatin is condensed. B, On activation, histones surrounding the Iε region are acetylated, chromatin is decondensed, and εGT is induced. C, Calcitriol stimulation leads to VDR-complex binding to Iε, which leads to chromatin condensation and εGT inhibition by means of histone deacetylation. Journal of Allergy and Clinical Immunology 2010 126, 1016-1023.e4DOI: (10.1016/j.jaci.2010.08.020) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Phenotype of CD23-enriched B cells Phenotype of CD23-enriched B cells. B cells were stimulated with anti-CD40/IL-4 with or without calcitriol for 48 hours. After purification of CD23+ B cells, expression of the surface molecules IgM, CD27, and CD23 was detected by means of flow cytometry. Data show a representative experiment of 3 identical experiments. Journal of Allergy and Clinical Immunology 2010 126, 1016-1023.e4DOI: (10.1016/j.jaci.2010.08.020) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Kinetics of VDR/RXRα binding to Iε and acetylation pattern Kinetics of VDR/RXRα binding to Iε and acetylation pattern. CD23+ cells were enriched after B-cell stimulation with anti-CD40/IL-4 with or without calcitriol for 48 hours. Calcitriol was additionally added at the time indicated. ChIP with antibodies against VDR (A), RXRα (B), AcH3 (C), and AcH4 (D) was performed, followed by amplification of Iε. Data are shown as the relative amount of antibody-bound DNA to unprecipitated DNA (n = 3-6). ∗P < .05. Journal of Allergy and Clinical Immunology 2010 126, 1016-1023.e4DOI: (10.1016/j.jaci.2010.08.020) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

VDR complex in the Iε region VDR complex in the Iε region. B cells were stimulated with anti-CD40/IL-4 with or without calcitriol for 48 hours. Calcitriol was additionally added for 90 minutes (A) or 180 minutes (B and C). CD23+ cells were isolated and ChIP was performed with antibodies against SMRT (Fig E3, A), HDAC1 (Fig E3, B), and HDAC3 (Fig E3, C). Amplification of Iε, the trpv6 promoter region (positive control), and the trpv6 orf (negative control) was analyzed by means of RT-PCR. Data are shown as the relative amount of antibody-bound DNA to unprecipitated DNA (means ± SEMs, n = 6). n.d., Not detectable. Journal of Allergy and Clinical Immunology 2010 126, 1016-1023.e4DOI: (10.1016/j.jaci.2010.08.020) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions