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J. Biol. Chem., Vol. 282, Issue 29, 20897-20905, July 20, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/29/20897    most recent M610038200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rogaeva, A. Articles by Albert, P. R. Search for Related Content PubMed PubMed Citation Articles by Rogaeva, A. Articles by Albert, P. R. Social Bookmarking                      What's this?

Differential Repression by Freud-1/CC2D1A at a Polymorphic Site in the Dopamine-D2 Receptor Gene^*

Anastasia Rogaeva¹, Xiao-Ming Ou², Hamed Jafar-Nejad^¶, Sylvie Lemonde³, and Paul R. Albert⁴

From the Ottawa Health Research Institute (Neuroscience) and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H-8M5, Canada, Department of Pharmacy, University of Southern California, Los Angeles, California 90033, and ^¶Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030

Freud-1/CC2D1A is a transcriptional repressor of the serotonin-1A receptor gene and was recently genetically linked to non-syndromic mental retardation. To identify new Freud-1 gene targets, data base mining for Freud-1 recognition sequences was done. A highly homologous intronic element (D2-DRE) was identified in the human dopamine-D2 receptor (DRD2) gene, and the role of Freud-1 in regulating the gene at this site was assessed. Recombinant Freud-1 bound specifically to the D2-DRE, and a major protein-D2-DRE complex was identified in nuclear extracts that was supershifted using Freud-1-specific antibodies. Endogenous Freud-1 binding to the D2-DRE in cells was detected using chromatin immunoprecipitation. The D2-DRE conferred strong repressor activity in transcriptional reporter assays that was dependent on the Freud-1 recognition sequence. In three different human cell lines, the level of Freud-1 protein was inversely related to DRD2 expression. Knockdown of endogenous Freud-1 using small interfering RNA resulted in an up-regulation of DRD2 RNA and binding sites, demonstrating a crucial role for Freud-1 in DRD2 regulation. A previously uncharacterized single nucleotide A/G polymorphism (rs2734836) was located adjacent to the D2-DRE and conferred allele-specific Freud-1 binding and repression, with the major G-allele having reduced activity. These studies demonstrate a key role for Freud-1 to regulate DRD2 expression and provide the first mechanistic insights into its transcriptional regulation. Allele-specific regulation of DRD2 expression by Freud-1 may possibly associate with psychiatric disorders or mental retardation.

Received for publication, October 26, 2006 , and in revised form, April 27, 2007.

^* This research was supported by grants from Canadian Institutes of Health Research and Ontario Mental Health Foundation (to P. R. A.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Recipient of a studentship from K. M. Hunter Charitable Foundation/Canadian Institutes of Health Research Doctoral Research Award and Ontario Graduate Scholarship.

² Recipient of a post-doctoral fellowship from Ontario Mental Health Foundation. Present address: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216.

³ Recipient of Canadian Institutes of Health Research Doctoral Research Award.

⁴ Recipient of the Novartis/Canadian Institutes of Health Research Michael Smith Chair in Neurosciences. To whom correspondence should be addressed: Ottawa Health Research Institute (Neuroscience) and Dept. of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, ON K1H-8M5, Canada. Tel.: 613-562-5800 (ext. 8307); Fax: 613-562-5403; E-mail: palbert{at}uottawa.ca.

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