Genome-wide principles of gene regulation by the vitamin D receptor and its activating ligand

The vitamin D receptor (VDR) mediates virtually all of the known biological actions of the hormonal ligand 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). These actions are directed toward the nucleus, where the VDR binds to the regulatory regions of target genes and modulates their transcriptional output. Recent technological advances have enabled the study of transcription factor binding on a genome-wide scale in cells and tissues that are major targets of vitamin D action. In this review, the results of several of these studies are discussed wherein overarching principles of gene regulation by the vitamin D hormone are beginning to emerge. In addition, several specific genes that are regulated by 1,25(OH)2D3 and which provide new insight into the increasingly complex mechanism whereby the receptor functions to modulate gene expression are considered. These studies suggest that while many of the principles that are now accepted regarding the regulation of gene expression by hormones and other regulatory factors are well grounded, others require extensive modification.

► Genome-scale analysis of VDR/RXR cistromes in cells reveals predominant ligand-dependent DNA binding interactions across the genome.
► Enhancers are located frequently both upstream and downstream of transcription units and within introns.
► The Cyp24a1 gene is regulated via both proximal and downstream enhancers.
► The Rankl gene is regulated by multiple distal enhancers located far upstream of the gene’s transcriptional start site.