The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights

Abstract

The vitamin D receptor (VDR) is the single known regulatory mediator of hormonal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in higher vertebrates. It acts in the nucleus of vitamin D target cells to regulate the expression of genes whose products control diverse, cell type-specific biological functions that include mineral homeostasis. In this Review we describe progress that has been made in defining new cellular sites of action of this receptor, the mechanisms through which this mediator controls the expression of genes, the biology that ensues, and the translational impact of this receptor on human health and disease. We conclude with a brief discussion of what comes next in understanding vitamin D biology and the mechanisms that underlie its actions.

Figure 1. Biological roles of the vitamin D hormone.

The three-dimensional structure of the vitamin D hormone is shown, with several of the major biological activities indicated.

Figure 2. Schematic of the mouse Tnfsf11 (RANKL) gene and its regulatory components.

Top: Locations of the upstream cis-acting regulatory components that control expression of the Tnfsf11 gene in mesenchymal and hematopoietic lineage cell types. The Tnfsf11 and Akap11 genes (with exons) are shown (arrows indicate direction of transcription), the locations of CTCF insulator elements are identified, and the locations of the individual Tnfsf11 enhancers (D1–D7 and T1–T3) are shown. Bottom: Hypothetical three-dimensional DNA looping organization of the Tnfsf11 gene and its engaged regulatory regions responsible for cell type–specific expression in mesenchymal/skeletal (left) and hematopoietic (right) cells. The spheres numbered 1–7 (left) represent the enhancer complexes and correspond to D1–D7 in the top figure. PP, proximal promoter.

Figure 3. Organization of the mouse Mmp13 gene and its regulatory components.

(A–D) Hypothetical three-dimensional looping organization of the Mmp13 gene in the absence (A) and fully engaged presence (B) of trans-acting regulatory factors, in the absence of the structural influence of the VDR-regulated –10-kb enhancer (C), and in the absence of the RUNX2-regulated –30-kb enhancer (D). GTA, general transcriptional apparatus; Pro, promoter region.