Vitamin D receptor (VDR) target genes in THP-1 monocytic leucemia cells. Homo sapiens

The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is a direct regulator of gene transcription, since it is the only high affinity natural ligand of the transcription factor vitamin D receptor (VDR). Transcriptome-wide analysis of THP-1 human monocyte-like cells had indicated more than 600 genes to be significantly (p < 0.05) regulated after a 4 h stimulation with 1,25(OH)2D3. In this study, we screened of the list of primary vitamin D targets for genes encoding for transcriptional regulators and selected those of the activating transcription factor NFE2 and the transcriptional repressor BCL6. Both genes are under the control of two VDR loci and are the only 1,25(OH)2D3 targets within their respective chromosomal domain. However, NFE2 mRNA was rapidly up-regulated, while the increase of BCL6 expression showed a slower rise. After 24 h incubation of THP-1 cells with 1,25(OH)2D3 more than 1,500 genes responded significantly (p < 0.001), of which 132 where more than 2-fold induced. Public chromatin immunoprecipitation-sequencing datasets suggested that the majority of these genes could be targets of NFE2 or BCL6. In time course experiments we displayed for representative gene examples the specific delayed response of secondary 1,25(OH)2D3 targets and confirmed for the respective chromosomal domains the genomic binding of NFE2, BCL6 and VDR. In conclusion, our study indicated that the physiological response of monocytes to 1,25(OH)2D3 involves the action of NFE2 and BCL6. Overall design: THP-1 cells were treated 24 h either with 0.1% ethanol (vehicle, control) or 1α,25(OH)2D3 (1,25D)