Ensembl Gene. Entrez Gene. Human Protein Atlas.
ENSG Hs. KEGG Gene.
RefSeq Nucleotide. RefSeq Protein.
- The coregulator exchange in transcriptional functions of nuclear receptors?
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- Pharmacology of nuclear receptor-coregulator recognition. - PubMed - NCBI.
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NR1I2 Hs. Selected 3D Structures. Key to terms and symbols. View all chemical structures. Click column headers to sort. Ligand Sp. Action Value Parameter Reference hyperforin. View species-specific agonist tables. Some environmental xenobiotics e. Action Value Parameter Reference trabectedin. It was thought the inhibitory effect may result from the cytotoxicity of this potent antineoplastic agent.
DNA Binding. Co-binding Partners. Main Co-regulators. Main Target Genes.
The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights
Our recent studies of the genome in bone cells and other cell types highlight some of the insights that have been gained regarding the properties of VDR interactions with the genome, including identification of VDR genetic targets, the consequences of VDR binding on gene output in response to 1,25 OH 2 D 3 , and the effects of differentiation on these features of VDR action refs.
Genome-wide analyses of osteoblast lineage cells beginning with mesenchymal stem cell MSC precursors and extending to osteoblasts and terminally differentiated osteocytes revealed VDR cistromes that are heavily dependent upon 1,25 OH 2 D 3 activation for broad DNA binding at sites of transcriptional regulation across the genome. While ligand-independent DNA binding occurs at limited locations in all of these osteoblast lineage cells, the number of sites that contain prebound RXR increases 8- to fold upon pretreatment with 1,25 OH 2 D 3. De novo analysis of the DNA sequences most overrepresented at these sites reveals the presence of one or more classic vitamin D response elements VDREs , each comprising two directly repeated imperfect hexameric half-sites separated by three base pairs.
These results confirm earlier traditional studies of single genes such as osteocalcin 62 , osteopontin 63 , and Cyp24a1 64 , the latter considered a quintessential and highly induced target of vitamin D action. As mentioned earlier, the vast majority of these VDR binding sites across osteoblast lineage cells were found within introns or intergenic regions either upstream or downstream many kilobases distal to transcriptional targets, sites that could not be identified by traditional methods. Analogous to the above discussion of VDR , we confirmed the functionality of many of these distal sites at known vitamin D target genes using large, genomically integrated segments of DNA 36 , 37 , 60 , 65 and via genomic deletion analyses 66 — 69 both in vitro and in vivo.
A classic example of a highly complex enhancer profile and of the factors that are associated with these regulatory sites is illustrated by Tnfsf11 the RANKL gene in Figure 2 , together with speculative looping profiles reviewed in ref. Importantly, while the presence of some of the enhancers previously identified near gene promoters using traditional means were confirmed by these unbiased methods, others were not, suggesting that traditional analyses in the absence of endogenous chromatin context can frequently result in false positives.
GENE EXPRESSION REGULATION AND TRANSCRIPTIONAL COREGULATORS
Many genes that rely upon promoter proximal elements were also regulated by more distal elements, as we showed for the Cyp24a1 gene Although cistromes for each of the cell types examined were highly cell specific overall, their general characteristics were common. Finally, most VDR-bound enhancers are modular and contain adjacent binding sites for additional transcription factors 49 , 50 , Importantly, treatment with 1,25 OH 2 D 3 altered the expression and genome-binding activity of these two factors following differentiation discussed below , thereby genetically influencing the gene-specific activity of vitamin D in a given cellular state.
This rather frequent functional regulatory unit unique to bone cells was termed a consolidated osteoblast enhancer complex In summary, these and other genome-wide analyses have not only confirmed many of the fundamental principles of vitamin D action identified earlier, but also provided new and unexpected insights. Top: Locations of the upstream cis -acting regulatory components that control expression of the Tnfsf11 gene in mesenchymal and hematopoietic lineage cell types.
The Tnfsf11 and Akap11 genes with exons are shown arrows indicate direction of transcription , the locations of CTCF insulator elements are identified, and the locations of the individual Tnfsf11 enhancers D1—D7 and T1—T3 are shown. The spheres numbered 1—7 left represent the enhancer complexes and correspond to D1—D7 in the top figure.
Nuclear Receptor Coregulators, Volume 68 - 1st Edition
PP, proximal promoter. VDR binding sites and transcriptional regulation. Although the presence of VDR binding sites in osteoblast lineage cells correlates with many genes that are regulated by 1,25 OH 2 D 3 , the VDR cistrome is far more complicated relative to transcriptional regulation. This is partly due to the distal nature of many VDR binding sites, making it difficult to link these regions directly to the genes they regulate based upon spatial proximity alone. Thus, while many genes located near VDR binding sites are regulated by 1,25 OH 2 D 3 , others similarly located are not 49 , Surprisingly, many genes regulated by 1,25 OH 2 D 3 do not contain VDR binding sites within or near their surrounding loci.
There are multiple explanations for these seemingly paradoxical results.
It is possible that the VDR is capable of binding to sites of historical significance earlier cellular states of differentiation. Binding sites may be located many hundreds of kilobases from the regulated gene at locations not readily identified. Alternatively, many genes may require the regulatory influence of additional signaling inputs for activation It is also possible that certain functional consequences of VDR binding cannot be recognized or that some sites may be nonfunctional.
Regardless of the explanation, these findings highlight the unexpected complexity that characterizes gene regulation when examined on a genome-wide scale in known target tissues and cells. The regulatory sites that mediate the actions of vitamin D as well as other regulatory hormones are highly dynamic. A comparison of the VDR cistromes in osteoblast lineage cells prior to and following differentiation into mature mineralizing osteoblasts in vitro 49 or in osteoblasts prior to and after their transition into terminally differentiated osteocytes 60 revealed striking changes to the genome after these cellular transitions.
Importantly, these changes correlate with similar changes in gene expression. In the case of the VDR cistrome, much of the restriction in VDR binding may be due to suppressed expression of the VDR gene itself, which results in a striking downregulation of VDR protein in more differentiated osteoblastic lineage cells This downregulation, which may result from the trophic effects of 1,25 OH 2 D 3 on VDR autoregulation in bone cells, also occurs in vivo.
This finding highlights the not unexpected fundamental importance of transcription factor expression to changes in transcriptomic output that can occur as a function of cellular differentiation; however, changes in cellular response to external cues are far more complex than just alterations in transcription factor expression.
The coregulator exchange in transcriptional functions of nuclear receptors
Interestingly, while many genes no longer responded to 1,25 OH 2 D 3 following osteoblast differentiation, a moderate cohort of genes exhibited unique patterns of response or acquired unusual sensitivity to 1,25 OH 2 D 3 Differentiation and changes in genetic factor expression. Mmp13 is relatively insensitive to induction by the vitamin D hormone in osteoblast lineage cells at early stages of development, but is strongly upregulated by the hormone following differentiation into mature mineralizing osteoblasts, particularly in chondrocytes 50 , Interestingly, each of these regions influenced basal Mmp13 expression.
Furthermore, while vitamin D response was uniquely mediated by a VDR-binding enhancer located 10 kb upstream, a RUNX2-bound enhancer located even further upstream at —30 kb exerted a hierarchical influence on the other enhancers and on the overall expression of Mmp13 While the activated reorganization of these dispersed enhancers is reminiscent of the more common consolidated versions, these results highlight the complexity inherent in the regulation of genes for which expression levels are controlled by more than one modulatory region.
This complexity may be particularly important for Mmp13 , a gene whose enzymatic product plays multiple structural and functional roles in a myriad of different tissues not limited to bone. Organization of the mouse Mmp13 gene and its regulatory components. A — D Hypothetical three-dimensional looping organization of the Mmp13 gene in the absence A and fully engaged presence B of trans -acting regulatory factors, in the absence of the structural influence of the VDR-regulated —kb enhancer C , and in the absence of the RUNX2-regulated —kb enhancer D.
GTA, general transcriptional apparatus; Pro, promoter region. Differentiation and changes in epigenetic modification.
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- Nuclear Receptor Coregulators: Volume 68 (Vitamins and Hormones)!
Differentiation may have the most profound impact on the epigenetic landscape across the genome and in particular at genetic loci that contain functional VDREs. On a genome-wide basis, we found that the histone H3 lysine 4 methylation, a histone modification that marks the general locations of regulatory enhancers 57 , was frequently either enriched or depleted as a function of differentiation; in some cases, this histone mark was newly commissioned at specific sites upon differentiation, suggesting that the initial lack of responsiveness to 1,25 OH 2 D 3 in pre-osteoblasts is due to restricted DNA access that is reversed as the cells undergo differentiation The dynamic nature of epigenetic modifications across the genome suggests that transcriptional regulation and therefore cellular phenotype may be much more plastic than previously thought.
In that vein, our recent studies of the epigenetic landscape of bone marrow—derived MSCs suggest an inherent epigenetic predisposition for osteoblastogenesis Thus, while MSCs can be prompted to undergo adipogenesis in response to an appropriate inducer cocktail in vitro, displaying an epigenetic profile that is distinct relative to osteoblasts, these adipocytes can be readily redirected into osteoblast-like cells following subsequent exposure to an osteogenic cocktail, perhaps via a trans-differentiation process.
Thus, differentiation influences the ability of cells to respond to signals via regulated modulators such as the VDR. The above mechanisms likely underlie the diverse biological effects of vitamin D that are exerted in a tissue- and cell type—specific fashion in all higher vertebrates. These include not only the role of vitamin D in mineral homeostasis through orchestrated actions on intestine, kidney, and bone, but also in immune cells, skin, and tissues of the cardiovascular system, muscle, liver, and brain.
Advances in our understanding of the multiple roles of vitamin D have been covered extensively in numerous reviews 13 , 76 — 81 and will not be considered in any depth here; however, it is noteworthy that the vast majority of the biological activities of the vitamin D hormone have emerged through either clinical discovery or through studies of the numerous genetically modified mouse models that have been created wherein either VDR or Cyp27b1 have been removed in tissues either globally or selectively 27 , 82 — Clinical observation of humans with mutant VDRs that underlie hereditary 1,25 OH 2 D 3 -resistant rickets HVDRR 85 — 87 presaged the creation of virtually all mutant VDR mouse models, many of which have been extensively described in recent reviews 76 , Indeed, the efficiency with which genetically modified mice can be made suggests that not only can they represent unique models for phenotypic analysis, but they may also serve as novel biological reagents designed to further our understanding of important mechanisms of transcriptional regulation.
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