Regulation of target gene expression by the vitamin D receptor - an update on mechanisms

Virtually all of the known biological actions of the hormonal ligand 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) are mediated by the vitamin D receptor (VDR). Following binding and activation by the ligand, the VDR localizes in the nucleus to the regulatory regions of target genes and recruits chromatin-active coregulatory complexes which, in turn, modulate transcriptional output. The failure of the VDR to function due to crippling mutations results in total hereditary resistance to 1,25(OH)(2)D-3 in both mice and humans. In this review, we summarize the structural and functional properties of the VDR and the role of 1,25(OH)(2)D-3 in receptor activation, and then describe the results of recent studies using genome-wide analyses that define the overarching principles through which the VDR modulates genes expression. We also focus on the recent analysis of a specific 1,25(OH)(2)D-3 regulated gene that provides confirmation of the principles identified through these genome-wide methodologies. Taken together, these studies suggest an unanticipated increase in the complexity of the molecular processes that govern gene regulation by hormones and other factors.