Diverse Regulation of Vitamin D Receptor Gene Expression by 1,25-Dihydroxyvitamin D and ATRA in Murine and Human Blood Cells at Early Stages of Their Differentiation

Abstract

Vitamin D receptor (VDR) is present in multiple blood cells, and the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is essential for the proper functioning of the immune system. The role of retinoic acid receptor α (RARα) in hematopoiesis is very important, as the fusion of RARα gene with PML gene initiates acute promyelocytic leukemia where differentiation of the myeloid lineage is blocked, followed by an uncontrolled proliferation of leukemic blasts. RARα takes part in regulation of VDR transcription, and unliganded RARα acts as a transcriptional repressor to VDR gene in acute myeloid leukemia (AML) cells. This is why we decided to examine the effects of the combination of 1,25D and all-trans-retinoic acid (ATRA) on VDR gene expression in normal human and murine blood cells at various steps of their development. We tested the expression of VDR and regulation of this gene in response to 1,25D or ATRA, as well as transcriptional activities of nuclear receptors VDR and RARs in human and murine blood cells. We discovered that regulation of VDR expression in humans is different from in mice. In human blood cells at early stages of their differentiation ATRA, but not 1,25D, upregulates the expression of VDR. In contrast, in murine blood cells 1,25D, but not ATRA, upregulates the expression of VDR. VDR and RAR receptors are present and transcriptionally active in blood cells of both species, especially at early steps of blood development.

The Vitamin D System in Humans and Mice: Similar but Not the Same

“…Some of them encode transcription factors involved in hematopoiesis [29,30], or proteins important for function of blood cells [31]. It has been also reported that VDR is present in multiple blood cells, including hematopoietic stem cells (HSC) in humans and in mice [9,32]. In VDR knockout mice, haematopoiesis and blood cell counts are normal, as long as the mice are kept in a pathogen-free environment.…”

“…The VDR gene in humans is located on chromosome 12 and spans about 100 kb of genomic DNA [40]. Its 5' regulatory region is very complex, and consists of seven untranslated exons (1a-1g) and three promoter regions [32]. Exon 1a is associated with a strong promoter and transcripts initiated in that site are the most common.…”

“…Exon 1a is associated with a strong promoter and transcripts initiated in that site are the most common. Expression of transcripts originating in exons 1c, 1f and 1g is tissue-specific: exon 1f transcripts were detected in kidney, parathyroid adenoma tissue and in intestinal cell line LIM1863 [41], exon 1g transcripts in normal blood and in KG1 leukemic cell line [32,42], while the activity of 1c promoter was identified only in breast cancer cells [43]. Since no distinct promoter activity was recognized for the region adjacent to exons 1d and 1g, it has been postulated that a single promoter upstream of 1a [44] or overlapping regions [41] regulate transcription from these exons.…”

Vitamin D and Haematopoiesis

“…The Vdr gene in mice has an organization that is simpler than that in humans, and differences lie in the untranslated exons and their promoters [41]. In consequence, ligand-activated VDR regulates the expression of murine Vdr, whilst ligand-activated RARα regulates the expression of human VDR rather than activated VDR [42,43].…”

Pathogenetic role of vitamin D deficiency in the development of menstrual dysfunction in pubertal girls: a literature review

“…Thus, a high incidence of vitamin D deficiency was revealed in carriers of VDR gene bb BsmI genotype of the polymorphic marker. It was shown that the carriage of polymorphic variants of genes was associated with different levels of serum vitamin D [25], and VDR Bsml gene polymorphism was significantly associated not only with vitamin D deficiency but also with insulin resistance [26].…”