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PMID:17426122

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Citation

Turunen, MM, Dunlop, TW, Carlberg, C and Väisänen, S (2007) Selective use of multiple vitamin D response elements underlies the 1 alpha,25-dihydroxyvitamin D3-mediated negative regulation of the human CYP27B1 gene. Nucleic Acids Res. 35:2734-47

Abstract

The human 25-hydroxyvitamin D3 (25(OH)D3) 1alpha-hydroxylase, which is encoded by the CYP27B1 gene, catalyzes the metabolic activation of the 25(OH)D3 into 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), the most biologically potent vitamin D3 metabolite. The most important regulator of CYP27B1 gene activity is 1alpha,25(OH)2D3 itself, which down-regulates the gene. The down-regulation of the CYP27B1 gene has been proposed to involve a negative vitamin D response element (nVDRE) that is located approximately 500 bp upstream from transcription start site (TSS). In this study, we reveal the existence of two new VDR-binding regions in the distal promoter, 2.6 and 3.2 kb upstream from the TSS, that bind vitamin D receptor-retinoid X receptor complexes. Since the down regulation of the CYP27B1 gene is tissue- and cell-type selective, a comparative study was done for the new 1alpha,25(OH)2D3-responsive regions in HEK-293 human embryonic kidney and MCF-7 human breast cancer cells that reflect tissues that, respectively, are permissive and non-permissive to the phenomenon of 1alpha,25(OH)2D3-mediated down-regulation of this gene. We found significant differences in the composition of protein complexes associated with these CYP27B1 promoter regions in the different cell lines, some of which reflect the capability of transcriptional repression of the CYP27B1 gene in these different cells. In addition, chromatin architecture differed with respect to chromatin looping in the two cell lines, as the new distal regions were differentially connected with the proximal promoter. This data explains, in part, why the human CYP27B1 gene is repressed in HEK-293 but not in MCF-7 cells.

Links

PubMed PMC1885674 Online version:10.1093/nar/gkm179

Keywords

25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism; Binding Sites; Calcitriol/pharmacology; Cell Line; Down-Regulation; Humans; Ligands; Promoter Regions, Genetic; Receptors, Calcitriol/metabolism; Transcription Factors/metabolism; Transcription, Genetic/drug effects; Vitamin D Response Element

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:VDR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P19793

F

Seeded From UniProt

complete

HUMAN:VDR

part_of

GO:0090575: RNA polymerase II transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:VDR

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:O15528)

Seeded From UniProt

complete

HUMAN:VDR

contributes_to

GO:0070644: vitamin D response element binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0002205)

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0070644: vitamin D response element binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0002205)

Seeded From UniProt

complete

HUMAN:RXRA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P11473

F

Seeded From UniProt

complete

HUMAN:RXRA

part_of

GO:0090575: RNA polymerase II transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RXRA

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:O15528)

Seeded From UniProt

complete

HUMAN:RXRA

part_of

GO:0043235: receptor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RXRA

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RXRA

enables

GO:0042809: vitamin D receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P11473

F

Seeded From UniProt

complete

HUMAN:RXRA

contributes_to

GO:0070644: vitamin D response element binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0002205)

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0070644: vitamin D response element binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:VDR

enables

GO:0046965: retinoid X receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P19793

F

Seeded From UniProt

complete

HUMAN:VDR

contributes_to

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:VDR

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

has_input:(UniProtKB:O15528)

Seeded From UniProt

complete

HUMAN:VDR

part_of

GO:0043235: receptor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:VDR

contributes_to

GO:0070644: vitamin D response element binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:VDR

part_of

GO:0090575: RNA polymerase II transcription factor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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