Vitamin D receptor binds to the ε germline gene promoter and exhibits transrepressive activity.

Abstract

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. 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. 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. We demonstrate that Iε is a possible VDR target. Calcitriol-activated VDR binds together with retinoid X receptor α 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. 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.