Abstract
Genome- and transcriptome-wide data has significantly increased the amount of available information about primary 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) target genes in cancer cell models, such as human THP-1 myelomonocytic leukemia cells. In this study, we investigated the genes G0S2, CDKN1A and MYC as master examples of primary vitamin D receptor (VDR) targets being involved in the control of cellular proliferation. The chromosomal domains of G0S2 and CDKN1A are 140–170 kb in size and contain one and three VDR binding sites, respectively. This is rather compact compared to the MYC locus that is 15 times larger and accommodates four VDR binding sites. All eight VDR binding sites were studied by chromatin immunoprecipitation in THP-1 cells. Interestingly, the site closest to the transcription start site of the down-regulated MYC gene showed 1,25(OH)2D3-dependent reduction of VDR binding and is not associated with open chromatin. Four of the other seven VDR binding regions contain a typical DR3-type VDR binding sequence, three of which are also occupied with VDR in macrophage-like cells. In conclusion, the three examples suggest that each VDR target gene has an individual regulatory scenario. However, some general components of these scenarios may be useful for the development of new therapy regimens.
Highlights
The hormonal form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), has the interesting property of directly activating one defined transcription factor, the vitamin D receptor (VDR) [1]
G0/G1 switch 2 (G0S2) and cyclin-dependent kinase inhibitor 1A (CDKN1A), because they were significantly up-regulated by 1,25(OH)2D3 and displayed one and three VDR peaks, respectively, in reasonable vicinity to their transcriptional start site (TSS) region
For the myelocytomatosis viral oncogene homolog (MYC) gene we identified even four VDR peaks, our microarray data did not indicate any significant regulation of the gene
Summary
The hormonal form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), has the interesting property of directly activating one defined transcription factor, the vitamin D receptor (VDR) [1]. VDR ChIP-seq was first reported for the immortalized B lymphocyte cell lines GM10855 and GM10861 (obtained from Caucasian female individuals of the HapMap project) [3], for the monocytic cell line THP-1 (derived from a male infant with acute myelomonocytic leukemia) [4], later for the colorectal adenocarcinoma cell line. The number of statistically significant VDR binding sites of the respective datasets varied between a few hundreds and more than 10,000, but only a low percentage of them are identical, when comparing two or more cellular models [8]. These models aim to cover the spectrum of responses to 1,25(OH)2D3 observed in health and disease. The immortalized cell models, lymphoblastoid and LX2 cells, essentially capture normal VDR signaling, while THP-1 leukemia cells display significant phenotypic responses towards 1,25(OH)2D3 exposure in terms of triggering differentiation
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