Genome-wide (over)view on the actions of vitamin D

For a global understanding of the physiological impact of the nuclear hormone 1α,25-dihydroxyvitamin D ₃ (1,25(OH) ₂D ₃) the analysis of the genome-wide locations of its high affinity receptor, the transcription factor vitamin D receptor (VDR), is essential. Chromatin immunoprecipitation sequencing (ChIP-seq) in GM10855 and GM10861 lymphoblastoid cells, undifferentiated and lipopolysaccharide-differentiated THP-1 monocytes, LS180 colorectal cancer cells and LX2 hepatic stellate cells revealed between 1000 and 13,000 VDR-specific genomic binding sites. The harmonized analysis of these ChIP-seq datasets indicates that the mechanistic basis for the action of the VDR is independent of the cell type. Formaldehyde-assisted isolation of regulatory elements sequencing (FAIRE-seq) data highlight accessible chromatin regions, which are under control of 1,25(OH) ₂D ₃. In addition, public data, such as from the ENCODE project, allow to relate the genome-wide actions of VDR and 1,25(OH) ₂D ₃ to those of other proteins within the nucleus. For example, locations of the insulator protein CTCF suggest a segregation of the human genome into chromatin domains, of which more than 1000 contain at least one VDR binding site. The integration of all these genome-wide data facilitates the identification of the most important VDR binding sites and associated primary 1,25(OH) ₂D ₃ target genes. Expression changes of these key genes can serve as biomarkers for the actions of vitamin D ₃ and its metabolites in different tissues and cell types of human individuals. Analysis of primary tissues obtained from vitamin D ₃ intervention studies using such markers indicated a large inter-individual variation for the efficiency of vitamin D ₃ supplementation. In conclusion, a genome-wide (over)view on the genomic locations of VDR provides a broader basis for addressing vitamin D's role in health and disease.