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J. Biol. Chem., Vol. 279, Issue 42, 43581-43588, October 15, 2004

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The Vitamin D Response Element in the Distal Osteocalcin Promoter Contributes to Chromatin Organization of the Proximal Regulatory Domain^*

Soraya Gutierrez, Jilin Liu, Amjad Javed, Martin Montecino¶, Gary S. Stein, Jane B. Lian, and Janet L. Stein||

From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655 and the ^¶Departamento de Bioquímica y Biología Molecular, Universidad de Concepcion, Concepcion 4079100, Chile

Vitamin D receptor (VDR) and Runx2 are key regulators of tissue-specific gene transcription. Using the bone-related osteocalcin (OC) gene, we have previously shown that Runx2 is required for the extensive chromatin remodeling that accompanies gene activation. Here, we have addressed the direct contribution of the VDR to chromatin remodeling events necessary for regulation of OC transcription using mutational analysis. Our studies demonstrate that both the distal and proximal DNase I-hypersensitive sites characteristic of the transcriptionally active OC promoter are not enhanced in the absence of a functional vitamin D response element (VDRE). Furthermore, restriction enzyme accessibility studies reveal that nucleosomal reorganization of the proximal promoter occurs in response to vitamin D and this reorganization is abrogated by mutation of the VDRE. These findings indicate that binding of liganded VDR in the distal promoter directly impacts the chromatin structure of the proximal promoter. We find that, in the absence of functional Runx sites, the VDR cannot be recruited to the OC promoter and, therefore, the VDRE is not competent to mediate vitamin D responsiveness. On the other hand, chromatin immunoprecipitation assays show that Runx2 association with the OC promoter is not significantly impaired when the VDRE is mutated. Chromatin immunoprecipitation assays also demonstrate that basal levels of histone acetylation occur in the absence of Runx2 binding but that the VDRE and vitamin D are required for enhanced acetylation of histones H3 and H4 downstream of the VDRE. Together our results support a stepwise model for chromatin remodeling of the OC promoter and show that binding of the liganded VDR·retinoid X receptor directly impacts both the distal and proximal regulatory domains.

Received for publication, July 22, 2004

^* This work was supported by National Institutes of Health Grants DE12528, R03TW00990, PO1AR48818, and P30DK32520. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. de Bioquímica y Biología Molecular, Universidad de Concepcion, Concepcion 4079100, Chile.

^|| To whom correspondence should be addressed: Dept. of Cell Biology, University of Massachusetts Medical School, 55 Lake Ave. N., Worcester, MA 01655-0106. Tel.: 508-856-5625; Fax: 508-856-6800; E-mail: janet.stein{at}umassmed.edu.

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