1,25-Dihydroxyvitamin D3 Controls a Cohort of Vitamin D Receptor Target Genes in the Proximal Intestine That Is Enriched for Calcium-regulating Components

Selective upregulation of the expression of plasma membrane calcium ATPase isoforms upon differentiation and 1,25(OH)2D3-vitamin treatment of colon cancer cells

“…Differentiation initiated by histone deacetylase inhibitors (e.g., butyrate, valerate or trichostatin A) resulted in the preferential up-regulation of PMCA4b expression [5,8]. [23,24,25,26,27,28,29,30,31]. However, no data were thus far available on the 1,25(OH) 2 D 3 -induced regulation of PMCA1 expression in human samples at protein level.…”

Biology and Mechanisms of Action of the Vitamin D Hormone

“…On the other hand, intestine specific transgenic expression of TRPV6 has been shown to result in a marked increase in intestinal calcium absorption and bone density in VDR-null mice, indicating a significant role for TRPV6 in the calcium absorptive process (55). Recent studies suggest the possibility that vitamin D-sensitive calcium uptake is achieved via a complex network of active calcium regulating components rather than through a single entity (56). It should also be noted that although the duodenum has been the focus of research related to 1,25(OH) 2 D 3 regulation of calcium absorption over many years, it is the distal intestine where the majority of ingested calcium is absorbed (57).…”

“…Examples of such distal elements for the VDR abound, but can be found in many of the genes whose putative promoter proximal elements were undetectable by ChIP-seq analysis. They include the mouse Tnfsf11 (RANKL) gene in bone cells where at least five intergenic regulatory regions for the VDR are located (62), the Cyp24a1 gene in numerous cell types where in addition to the well-known promoter proximal element discussed above, a complex downstream cluster of regulatory elements exists in both the mouse and the human genes (43), the Vdr gene in bone cells where both upstream regulatory regions and several intronic elements are present (127,151), the TRPV6 gene in intestinal cells which contains multiple upstream elements (56,152), the S100g gene in the intestine which also contains multiple upstream elements (56), and the many target genes such as c-FOS and c-MYC in human colorectal cancer cells as well (149). Indeed, enhancers for other transcription factors have been identified more than a megabase from the genes they are known to regulate, although at present the most distal VDR binding site is 335 kb upstream of the human c-MYC promoter.…”

The vitamin D receptor functions as a transcription regulator in the absence of 1,25-dihydroxyvitamin D3

“…Indeed, PTH profoundly upregulates the expression of renal Cyp27b1 to increase the production of 1,25(OH) 2 D 3 which in turn activates the VDR [2]. 1,25(OH) 2 D 3 -bound VDR modulates the expression of a network of genes to raise calcium absorption in intestine [3] while influencing bone cell differentiation in conjunction with PTH to affect bone remodeling [4]. Increased levels of 1,25(OH) 2 D 3 also exert a suppressive negative feedback loop in the PTG to reduce the production of PTH, although the molecular mechanism of such action remains unclear [5].…”

“…Our recent unbiased genome-wide studies using ChIP-sequencing (ChIP-seq) analysis coupled with to RNA-sequencing (RNA-seq) analysis in bone cells [11] and mouse small intestine [3] suggest that VDR binding sites are enriched for VDREs but also contain adjacent sequences capable of interacting with additional transcription factors that may be involved. These studies have also revealed that 1,25(OH) 2 D 3 /VDR target genes are regulated through multiple enhancers located predominantly within introns and intergenic regions but less frequently in regions near target gene promoters.…”