The first genome-wide view of vitamin D receptor locations and their mechanistic implications

The transcription factor vitamin D receptor (VDR) is the nuclear sensor for the biologically most active metabolite of vitamin D, 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)). The physiological actions of the VDR and its ligand are not only the well-known regulation of calcium and phosphorus uptake and transport controlling bone formation, but also their significant involvement in the control of immune functions and of cellular growth and differentiation. For a general understanding of the mechanisms of 1α,25(OH)(2)D(3) signaling, it is essential to monitor the genome-wide location of VDR in relation to primary 1α,25(OH)(2)D(3) target genes. Within the last months, two chromatin immunoprecipitation sequencing (ChIP-Seq) studies using cells of the hematopoietic system, lymphoblastoids and monocytes, were published. The reports indicated the existence of 2776 and 1820 1α,25(OH)(2)D(3)-stimulated VDR-binding sites, comparable numbers, of which, however, only 18.2% overlapped. The two studies were very different in their 1α,25(OH)(2)D(3) treatment times (36 h versus 40 min), but showed consensus in identifying response elements formed by a direct repeat of two hexameric binding sites with three intervening nucleotide (DR3) as major DNA contact sites of the VDR. Interestingly, when analyzed in the same way, both reports indicated that within 100 bp of their VDR ChIP-Seq peak summits only fewer than 40% contain a DR3-type response element. This review provides a detailed comparison of the insights obtained from both ChIP-Seq studies.