Abstract
Vitamin D3 is an essential micronutrient mediating pleiotropic effects in multiple tissues and cell types via its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), which activates the transcription factor vitamin D receptor. In this study, we used peripheral blood mononuclear cells (PBMCs) obtained from five healthy adults and investigated transcriptome-wide, whether the precursor of 1,25(OH)2D3, 25-hydroxyvitamin D3 (25(OH)D3), has gene regulatory potential on its own. Applying thresholds of >2 in fold change of gene expression and <0.05 as a false discovery rate, in this ex vivo approach the maximal physiological concentration of 25(OH)D3 (250 nM (nmol/L)) none of the study participants had a significant effect on their PBMC transcriptome. In contrast, 1000 and 10,000 nM 25(OH)D3 regulated 398 and 477 genes, respectively, which is comparable to the 625 genes responding to 10 nM 1,25(OH)2D3. The majority of these genes displayed specificity to the tested individuals, but not to the vitamin D metabolite. Interestingly, the genes MYLIP (myosin regulatory light chain interacting protein) and ABCG1 (ATP binding cassette subfamily G member 1) showed to be specific targets of 10,000 nM 25(OH)D3. In conclusion, 100- and 1000-fold higher 25(OH)D3 concentrations than the reference 10 nM 1,25(OH)2D3 are able to affect the transcriptome of PBMCs with a profile comparable to that of 1,25(OH)2D3.
Highlights
From our own experience [19,43] and the literature [44], we know that the number of regulated genes obtained by transcriptome-wide analysis largely depends on threshold settings, both in minimal changes of expression (FC) as well as on the chosen statistical approach
We applied the rather rigorous statistical test of glmTreat [32,33] using thresholds of fold change (FC) > 2 and FDR < 0.05 in order to focus on reliably regulated genes
We observed that neither a 25(OH)D3 concentration of 100 nM nor 250 nM, which are both within the physiological range, resulted in peripheral blood mononuclear cells (PBMCs) of any of the study participants in a significant regulation of genes
Summary
In winter months at latitudes above 40◦ UV-B, radiation is insufficient for endogenous production of vitamin D3 [2]. Under these conditions, the molecule is a real vitamin, which needs to be taken up, in order to keep the vitamin D status at levels that are acceptable for maintaining its disease protective function. Vitamin D insufficiency is associated with a number of immunological disorders, such as multiple sclerosis [5], rheumatoid arthritis [6], inflammatory bowel disease [7], type I diabetes [8], and increases the risk for severe consequences from infections with mycobacterium tuberculosis [9], influenza virus or severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) [10,11]. In order to avoid these risks, the vitamin D status is recommended to be in the order of 100 nM
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