1α,25-dihydroxy vitamin D3-enhanced expression of the osteocalcin gene involves increased promoter occupancy of basal transcription regulators and gradual recruitment of the 1α,25-dihydroxy vitamin D 3 receptor-SRC-1 coactivator complex

Loreto Carvallo, Berta Henríquez, Roberto Paredes, Juan Olate, Sergio Onate, Andre J. Van Wijnen, Jane B. Lian, Gary S. Stein, Janet L. Stein, Martin Montecino

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Binding of 1α,25-dihydroxy vitamin D3 to the C-terminal ligand-binding domain (LBD) of its receptor (VDR) induces a conformational change that enables interaction of VDR with transcriptional coactivators such as members of the p160/SRC family or the DRIP (vitamin D receptor-interacting complex)/Mediator complex. These interactions are critical for VDR-mediated transcriptional enhancement of target genes. The p160/SRC members contain intrinsic histone acetyl transferase (HAT) activities that remodel chromatin at promoter regulatory regions, and the DRIP/Mediator complex may establish a molecular bridge between the VDR complex and the basal transcription machinery. Here, we have analyzed the rate of recruitment of these coactivators to the bone-specific osteocalcin (OC) gene in response to short and long exposures to 1α,25-dihydroxy vitamin D3. We report that in intact osteoblastic cells VDR, in association with SRC-1, rapidly binds to the OC promoter in response to the ligand. The recruitment of SRC-I correlates with maximal transcriptional enhancement of the OC gene at 4 h and with increased histone acetylation at the OC promoter. In contrast to other 1α,25-dihydroxy vitamin D3-enhanced genes, binding of the DRIP205 subunit, which anchors the DRIP/Mediator complex to the VDR, is detected at the OC promoter only after several hours of incubation with 1α,25-dihydroxy vitamin D3, concomitant with the release of SRC-1. Together, our results support a model where VDR preferentially recruits SRC-1 to enhance bone-specific OC gene transcription.

Original languageEnglish (US)
Pages (from-to)740-749
Number of pages10
JournalJournal of Cellular Physiology
Volume214
Issue number3
DOIs
StatePublished - Mar 2008
Externally publishedYes

Fingerprint

Calcitriol Receptors
Osteocalcin
Transcription
Genes
Mediator Complex
Gene Expression
Histones
Mediator Complex Subunit 1
Bone
Ligands
Bone and Bones
Acetylation
Nucleic Acid Regulatory Sequences
Transferases
Anchors
Genetic Promoter Regions
Chromatin
Machinery
dihydroxy-vitamin D3
Association reactions

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

1α,25-dihydroxy vitamin D3-enhanced expression of the osteocalcin gene involves increased promoter occupancy of basal transcription regulators and gradual recruitment of the 1α,25-dihydroxy vitamin D 3 receptor-SRC-1 coactivator complex. / Carvallo, Loreto; Henríquez, Berta; Paredes, Roberto; Olate, Juan; Onate, Sergio; Van Wijnen, Andre J.; Lian, Jane B.; Stein, Gary S.; Stein, Janet L.; Montecino, Martin.

In: Journal of Cellular Physiology, Vol. 214, No. 3, 03.2008, p. 740-749.

Research output: Contribution to journalArticle

Carvallo, Loreto ; Henríquez, Berta ; Paredes, Roberto ; Olate, Juan ; Onate, Sergio ; Van Wijnen, Andre J. ; Lian, Jane B. ; Stein, Gary S. ; Stein, Janet L. ; Montecino, Martin. / 1α,25-dihydroxy vitamin D3-enhanced expression of the osteocalcin gene involves increased promoter occupancy of basal transcription regulators and gradual recruitment of the 1α,25-dihydroxy vitamin D 3 receptor-SRC-1 coactivator complex. In: Journal of Cellular Physiology. 2008 ; Vol. 214, No. 3. pp. 740-749.
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AU - Carvallo, Loreto

AU - Henríquez, Berta

AU - Paredes, Roberto

AU - Olate, Juan

AU - Onate, Sergio

AU - Van Wijnen, Andre J.

AU - Lian, Jane B.

AU - Stein, Gary S.

AU - Stein, Janet L.

AU - Montecino, Martin

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N2 - Binding of 1α,25-dihydroxy vitamin D3 to the C-terminal ligand-binding domain (LBD) of its receptor (VDR) induces a conformational change that enables interaction of VDR with transcriptional coactivators such as members of the p160/SRC family or the DRIP (vitamin D receptor-interacting complex)/Mediator complex. These interactions are critical for VDR-mediated transcriptional enhancement of target genes. The p160/SRC members contain intrinsic histone acetyl transferase (HAT) activities that remodel chromatin at promoter regulatory regions, and the DRIP/Mediator complex may establish a molecular bridge between the VDR complex and the basal transcription machinery. Here, we have analyzed the rate of recruitment of these coactivators to the bone-specific osteocalcin (OC) gene in response to short and long exposures to 1α,25-dihydroxy vitamin D3. We report that in intact osteoblastic cells VDR, in association with SRC-1, rapidly binds to the OC promoter in response to the ligand. The recruitment of SRC-I correlates with maximal transcriptional enhancement of the OC gene at 4 h and with increased histone acetylation at the OC promoter. In contrast to other 1α,25-dihydroxy vitamin D3-enhanced genes, binding of the DRIP205 subunit, which anchors the DRIP/Mediator complex to the VDR, is detected at the OC promoter only after several hours of incubation with 1α,25-dihydroxy vitamin D3, concomitant with the release of SRC-1. Together, our results support a model where VDR preferentially recruits SRC-1 to enhance bone-specific OC gene transcription.

AB - Binding of 1α,25-dihydroxy vitamin D3 to the C-terminal ligand-binding domain (LBD) of its receptor (VDR) induces a conformational change that enables interaction of VDR with transcriptional coactivators such as members of the p160/SRC family or the DRIP (vitamin D receptor-interacting complex)/Mediator complex. These interactions are critical for VDR-mediated transcriptional enhancement of target genes. The p160/SRC members contain intrinsic histone acetyl transferase (HAT) activities that remodel chromatin at promoter regulatory regions, and the DRIP/Mediator complex may establish a molecular bridge between the VDR complex and the basal transcription machinery. Here, we have analyzed the rate of recruitment of these coactivators to the bone-specific osteocalcin (OC) gene in response to short and long exposures to 1α,25-dihydroxy vitamin D3. We report that in intact osteoblastic cells VDR, in association with SRC-1, rapidly binds to the OC promoter in response to the ligand. The recruitment of SRC-I correlates with maximal transcriptional enhancement of the OC gene at 4 h and with increased histone acetylation at the OC promoter. In contrast to other 1α,25-dihydroxy vitamin D3-enhanced genes, binding of the DRIP205 subunit, which anchors the DRIP/Mediator complex to the VDR, is detected at the OC promoter only after several hours of incubation with 1α,25-dihydroxy vitamin D3, concomitant with the release of SRC-1. Together, our results support a model where VDR preferentially recruits SRC-1 to enhance bone-specific OC gene transcription.

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