Abstract
Vitamin D3 has transcriptome- and genome-wide effects and activates, via the binding of its metabolite 1α,25-dihydroxyvitamin D3 to the transcription factor vitamin D receptor (VDR), several hundred target genes. Using samples from a 5-month vitamin D3 intervention study (VitDmet), we recently reported that the expression of 12 VDR target genes in peripheral blood mononuclear cells (PBMCs) as well as 12 biochemical and clinical parameters of the study participants are significantly triggered by vitamin D3. In this study, we performed a more focused selection of further 12 VDR target genes and demonstrated that changes of their mRNA expression in PBMCs of VitDmet subjects significantly correlate with alterations of 25-hydroxyvitamin D3 serum levels. Network and self-organizing map analysis of these datasets together with that of the other 24 parameters was followed by relevance calculations and identified changes in parathyroid hormone serum levels and the expression of the newly selected genes STS, BCL6, ITGAM, LRRC25, LPGAT1 and TREM1 as well as of the previously reported genes DUSP10 and CD14 as the most relevant parameters for describing vitamin D responsiveness in vivo. Moreover, parameter relevance ranking allowed the segregation of study subjects into high and low responders. Due to the long intervention period the vitamin D response was not too prominent on the level of transcriptional activation. Therefore, we performed in the separate VitDbol trial a short-term but high dose stimulation with a vitamin D3 bolus. In PBMCs of VitDbol subjects we observed direct transcriptional effects on the selected VDR target genes, such as an up to 2.1-fold increase already one day after supplementation onset. In conclusion, both long-term and short-term vitamin D3 supplementation studies allow monitoring the vitamin D responsiveness of human individuals and represent new types of human in vivo vitamin D3 investigations.
Highlights
Vitamin D3 is an important endocrine compound that has genome- and transcriptome-wide effects on most human tissues and cell types [1,2]
Based on information provided by i) a harmonized re-analysis of vitamin D receptor (VDR) ChIP-seq data from the human B cell lines GM10855 and GM10861, human monocytic THP-1 cells and human macrophage-like LPS-differentiated THP-1 cells [21] and ii) a microarray of undifferentiated THP1 cells that were treated for 24 h with 1,25(OH)2D3 [19], we selected the 12 VDR target genes STS, B-cell CLL/lymphoma 6 (BCL6), ITGAM, leucine rich repeat containing 25 (LRRC25), lysophosphatidylglycerol acyltransferase 1 (LPGAT1), triggering receptor expressed on myeloid cells 1 (TREM1), CD274, FUCA1, NFE2, CD38, FBP1 and transmembrane protein 37 (TMEM37) (S1 Fig) for expression studies in human peripheral blood mononuclear cells (PBMCs)
The selection criteria for the genes were that i) they carry in distance of less than 250 kb from their transcription start site (TSS) a genomic VDR binding site that is in at least two hematopoietic cell models occupied by the receptor, ii) their expression in THP-1 cells was at least 2-fold induced after 24 h treatment with VDR ligand [19] and iii) they show reasonable basal expression in human PBMCs
Summary
Vitamin D3 is an important endocrine compound that has genome- and transcriptome-wide effects on most human tissues and cell types [1,2]. The biologically most active vitamin D compound is 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), which functions as specific high-affinity ligand of the transcription factor VDR [5]. Humans should aim for an optimal vitamin D status, in order to take full benefit from the potential of the pleiotropic signaling molecule. There are high inter-individual variations in serum 25(OH)D3 levels due to different exposure to natural UV-B radiation or intake of vitamin D3 from diet or supplements. The vitamin D status was found to be associated with age, body mass index and (epi)genetic polymorphisms [9,10,11]. The bone health of these individuals is compromised, but they have an increased risk of developing a number of diseases, such as cancer, autoimmune disorders and various features of the metabolic syndrome [14]
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