Abstract
(1) Background: Vitamin D receptor (VDR) is present in multiple types of blood cells, and its ligand, 1,25-dihydroxyvitamin D (1,25D), is important for the proper functioning of the immune system. Activity of VDR is higher in hematopoietic stem and progenitor cells than in fully differentiated blood cells of mice and humans. In some human acute myeloid leukemia (AML) blasts, the expression of the VDR gene is also high. The mechanism of silencing the VDR gene expression during differentiation of blood cells has been addressed in this work. (2) Methods: The cells have been obtained using fluorescence activated sorting from murine tissues and from human umbilical cord blood (UCB). Then, the expression of the VDR gene and transcriptional activity of the VDR protein has been tested in real-time polymerase chain reaction (PCR). Eventually, the methylation of VDR promoter regions was tested using bisulfite sequencing. (3) Results: The CpG islands in VDR promoters were not methylated in the cells studied both in mice and in humans. The use of hypomethylating agents had no effect toward expression of human VDR transcripts, but it increased expression of the VDR-target gene, CYP24A1. (4) Conclusions: The expression of the VDR gene and transcriptional activity of the VDR protein varies at successive stages of hematopoietic differentiation in humans and mice, and in blasts from AML patients. The experiments presented in this case indicate that methylation of the promoter region of the VDR gene is not the major mechanism responsible for these differences.
Highlights
The vitamin D receptor (VDR) belongs to the super-family of nuclear receptors, which function as ligand-activated transcriptional regulators [1]. 1,25-Dihydroxyvitamin D (1,25D) is a natural ligand for VDR, and the 1,25D-VDR complex regulates transcription of approximately 3% of mammalian genes [2]
Since the transcriptional activity of VDR protein was significantly higher in murine hematopoietic stem and progenitor cells (HSPCs) than
Since the transcriptional activity of VDR protein was significantly higher in murine HSPCs than in fully differentiated blood cells [8], we hypothesized that epigenetic silencing of Vdr gene expression in fully differentiated blood cells [8], we hypothesized that epigenetic silencing of Vdr gene mayexpression underlie the observed identified a CpG
Summary
The vitamin D receptor (VDR) belongs to the super-family of nuclear receptors, which function as ligand-activated transcriptional regulators [1]. 1,25-Dihydroxyvitamin D (1,25D) is a natural ligand for VDR, and the 1,25D-VDR complex regulates transcription of approximately 3% of mammalian genes [2]. The most important function of the 1,25D-VDR system is the maintenance of healthy bones by regulating calcium-phosphate homeostasis [3]. It has been documented that VDR is present and transcriptionally active in human and murine hematopoietic stem and progenitor cells (HSPCs) [8]. The protein level and transcriptional activity of VDR is higher in HSPCs than in differentiated blood cells, and is higher in monocytes than in other lineages [8,12]. It is, interesting how the expression of the gene encoding VDR is being silenced during differentiation of certain hematopoietic pathways
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