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 D3 receptor-SRC-1 coactivator complex

✍ Scribed by 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

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 289 KB
• Volume: 214
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21267

✦ Synopsis

Abstract

Binding of 1α,25‐dihydroxy vitamin D~3~ 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 D~3~. 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‐1 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 D~3~‐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 D~3~, 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. J. Cell. Physiol. 214: 740–749, 2008. © 2007 Wiley‐Liss, Inc.