Vitamin D receptor signaling mechanisms: integrated actions of a well-defined transcription factor

Abstract

The main physiological actions of the biologically most active metabolite of vitamin D, 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)), are calcium and phosphorus uptake and transport and thereby controlling bone formation. Other emergent areas of 1α,25(OH)(2)D(3) action are in the control of immune functions, cellular growth and differentiation. All genomic actions of 1α,25(OH)(2)D(3) are mediated by the transcription factor vitamin D receptor (VDR) that has been the subject of intense study since the 1980's. Thus, vitamin D signaling primarily implies the molecular actions of the VDR. In this review, we present different perspectives on the VDR that incorporate its role as transcription factor and member of the nuclear receptor superfamily, its dynamic changes in genome-wide locations and DNA binding modes, its interaction with chromatin components and its primary protein-coding and non-protein coding target genes and finally how these aspects are united in regulatory networks. By comparing the actions of the VDR, a relatively well-understood and characterized protein, with those of other transcription factors, we aim to build a realistic positioning of vitamin D signaling in the context of other intracellular signaling systems.

Fig. 1

VDR binding sites and target genes. (A) The crystal structure (protein data bank identifier 1YNW [112]) of the heterodimer of the DBDs of VDR (blue) and RXR (red) bound to a DR3-type RE (top) is aligned with the de novo DR3-type sequence motif found below 742 of 2340 VDR peaks (31.7%) in THP-1 cells [35] (bottom). (B) Three modes of VDR regulating its primary target genes are indicated: VDR–RXR heterodimers preferentially binding to a DR3-type RE (top), VDR partnering with undefined protein X bound to DNA (middle) and VDR tethering undefined protein X bound to DNA (bottom). In all three cases it is assumed that the contact of ligand (red)-activated VDR leads to an association with CoA proteins and the activation of primary target genes. (C) The genome view of one primary VDR target gene, CYP19A1, is shown. The peak tracks on top show data from VDR ChIP-seq in LS-180 cells (pink [36]), lymphoblastoids (blue [34]) and THP-1 cells (red [35]) comparing genomic VDR binding at the CYP19A1 locus in unstimulated or vehicle-stimulated cells with that after 1α,25(OH)₂D₃ (1,25D) treatment for indicated times. The structure of CYP19A1 gene and its direct neighbor GLDN is shown in blue and the sequence of the DR3-type VDRE at the summit of the VDR ChIP-seq peak is indicated.

Fig. 2

Integration of VDR actions. Together with the pioneering factors the VDR is the central part of a differentiation module. Putative pioneer factors such as CEBPA and SPI1 appear to help the VDR to access to its genomic binding sites, but may not be found at all VDR binding loci. At these genomic VDR binding regions there is a cyclical alternation of proteins representing the deactivation phase (for example, CoRs and HDACs), the activation phase (for example, CoAs and HATs) and the initiation phase (for example, VDR and Mediator proteins). The outcome of the dynamic interaction of VDR with its binding sites and partner proteins is the modulation of the transcription of its primary target genes. The latter are either protein coding genes or non-coding genes, such as miRNA genes. Some of the miRNAs are involved in the fine-tuning of the mRNA expression of the protein-coding genes. Together with secondary target genes they mediate the physiological actions of 1α,25(OH)₂D₃ and its receptor VDR.