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

Abstract

The vitamin D receptor (VDR) mediates virtually all of the known biological actions of the hormonal ligand 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). 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)(2)D(3) 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.

Figure 1

Relative VDR and RXR binding activities across mouse and human genomes in the absence and presence of 1,25(OH)₂D₃.

Figure 2

Position weight matrix motif (VDRE) derived from 168 VDR/RXR binding sites in human colorectal cancer cells.

Figure 3

Possible locations of regulatory enhancers across mammalian genomes. Promoters, enhancers, exons, and the direction of transcription is shown. Examples of genes that display the indicated configuration from the top to the botton panel are as follow: 1) CYP24A1, 2) VDR, 3) TRPV6 and c-FOS, 4) CYP24A1, 5) RANKL, and 6) c-MYC and PAX6.

Figure 4

Locations of active regulatory enhancers for the (A) human CYP24a1 and (B) mouse Tnfsf11 (Rankl) genes. The individual transcription units and their associated exons and introns are shown with the arrow indicating the promoter and the direction of transcription. The positions of CTCF/RAD21 binding sites are designated with arrows. The Tnfsf11 enhancers D1-D7 and their positions relative to the gene’s transcriptional start site (TSS) are documented. The TSS, promoter proximal and downstream enhancer cluster for the CYP24A1 gene are indicated.