## 3 Vitamin D and Its Receptor VDR  
The active form of vitamin D3 is the 1\(\alpha\),25-dihydroxyvitamin D3, or calcitriol (also addressed as vitamin D in this review), which is obtained after the double hydroxylation of the precursor on C-25 and on C-1; these reactions take place in the liver and in the kidney, respectively, and are catalyzed by cytochrome P-450 enzymes (CYP). Kidney, as well as many tissues, is the site of both the final activation step and the degradation of calcitriol to the inactive 24,25-dihydroxyvitamin D and 1,24,25-trihydroxyvitamin D metabolites. Vitamin D acts through the binding to the vitamin D receptor (VDR) that drives the expression of VDR responsive genes. In addition to the tissues involved in calcium and phosphate homeostasis, the entire organism is affected by vitamin D activity (extensively reviewed in [37]). VDR is mostly expressed in colon and skin epithelial cells; in colon cells vitamin D-VDR induces the expression of transcription factors, immunomodulators, anti-inflammatory, and anti-oxidant effectors [37]. Vitamin D controls the expression of hundreds of different genes: At the same time it activates some key genes and represses others, inhibiting growth and promoting cell differentiation. VDR is a trans-acting transcription factor, a member of the nuclear receptor family. It is encoded by VDR gene which shares a high sequence similarity with steroid and thyroid hormone receptors. Vitamin D responsive genes contain multiple VDRE sites (vitamin D responsive elements) and usually just one of them is in the proximal promoter region, whereas the others are dispersed up to 100 kb downstream and upstream from the transcription initiation site. The individual VDREs seem to function synergistically in attracting co-modulators; all the docking sites need to be occupied in order to have the maximal induction of response. These distant regions are juxtaposed via chromatin looping, creating a single platform where the transcription machinery assembles (reviewed in [38; 39]). Genes responsive to vitamin D-VDR can be divided into several groups according to their biological function: They can be involved in bone metabolism, anabolism and resorption, mineral homeostasis, cell life (including proliferation, differentiation, migration, and death), immune modulation, and metabolism. For further details on the transcriptional activity of vitamin D, the reader is referred to very comprehensive reviews [37; 40]. The transcription of these genes depends on the presence of the hormone, which binds VDR inducing a critical conformational change in the C terminal region from the closed conformation to the open one; the latter allows the binding to co-activators that stabilize VDR-RXR (retinoid X receptor) complex and the docking to VDREs. However, the chromatin condensation changes from tissue to tissue, so that in different tissues various VDREs can be bound by VDR-RXR active complex; the ensemble of all the genomic cis targets open to VDR docking is called VDR cistrome. ChIP-sequencing datasets analysis identified more than 23,000 unique VDR binding sites, 75% of which represent a cell type specific binding profile [41]. The ligand binding increases DNA docking of VDR by a factor of 2.5 [42]. These data demonstrate that the VDR cistrome can be modulated by the binding of calcitriol or other molecules. The expression of VDR and the presence of vitamin D are necessary but not sufficient to trigger the transcription of VDR target genes. In fact also the level of chromatin accessibility in the VDRE regions impacts on the transcription of vitamin D induced genes; if VDREs are within a hypermethylated region of heterochromatin they are not accessible and thus cannot be bound by the active form of VDR-RXR. This highly specific epigenetic regulation of VDR cistrome is one of the main principles that ensure tissue-specific gene expression.