Vitamin D receptor binds to the ε germline gene promoter and exhibits transrepressive activity - 07/08/11
, Werner Hallatschek, PhD b, Bastian Opitz, MD b, Andreas Radbruch, PhD c, Margitta Worm, MD a, ⁎ 
Reprint requests: Margitta Worm, MD, Allergy-Center-Charité, CCM, Department of Dermatology and Allergy, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.Abstract |
Background |
Recently, an increased incidence of allergic diseases has been associated with vitamin D deficiency. We demonstrated previously that calcitriol, the active form of vitamin D, inhibits ε germline transcription, a prerequisite for IgE production. However, the underlying mechanisms remain unexplored.
Objective |
We sought to investigate whether the ε germline gene promoter (Iε) represents a primary vitamin D receptor (VDR) target. Therefore we investigated VDR binding to Iε, analyzed VDR-complex composition in more detail, and delineated its functional consequences.
Methods |
The VDR binding to Iε in human B cells, the composition of the VDR-recruited complex, and the acetylation pattern were investigated by means of chromatin immunoprecipitation. The calcitriol-mediated action on Iε was analyzed by using a reporter gene assay.
Results |
We demonstrate that Iε is a possible VDR target. Calcitriol-activated VDR binds together with retinoid X receptor ⍺ to the Iε region. The heterodimer interacts with silencing mediator for retinoid and thyroid hormone receptors, which recruits histone deacetylase (HDAC) 1 and HDAC3. The inhibition of silencing mediator for retinoid and thyroid hormone receptors or HDACs reversed the site-specific deacetylation of histones 3 and 4 and the calcitriol-driven inhibition of the ε germline transcription. The VDR-complex transrepressive actions on Iε were confirmed in a reporter assay.
Conclusion |
We show here that inhibition of IgE production by calcitriol is mediated by its transrepressive activity through the VDR-corepressor complex affecting chromatin compacting around the Iε region. Our findings shed new light on mechanisms of VDR transrepression and understanding of IgE regulation.
Le texte complet de cet article est disponible en PDF.Key words : Vitamin D receptor, calcitriol, ε germline transcript, class-switch recombination, IgE, histone acetylation
Abbreviations used : AcH, As2O3, CH, ChIP, CSR, CYP27B1, GLT, GT, HDAC, Iε, NCoR, orf, qRT-PCR, RAR, RXR, SMRT, SNP, trpv6, TSS, VDR, VDRE
Plan
| Supported in part by the Deutsche Forschungsgemeinschaft (DFG–SFB650 TP5). Milena Milovanovic received a scholarship from the NaFöG-Promotionsförderung des Landes Berlin. |
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| Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. |
Vol 126 - N° 5
P. 1016 - novembre 2010 Retour au numéro
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