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J. Biol. Chem., Vol. 282, Issue 37, 26717-26724, September 14, 2007

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Regulation of Tryptophan Hydroxylase-2 Gene Expression by a Bipartite RE-1 Silencer of Transcription/Neuron restrictive Silencing Factor (REST/NRSF) Binding Motif^*

Paresh D. Patel¹, Daniel A. Bochar, David L. Turner, Fan Meng², Helena M. Mueller, and Crystal G. Pontrello^¶

From the Molecular and Behavioral Neuroscience Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109-2200, Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0606, and ^¶Program in Neuroscience, University of California, Riverside, California 92521

Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme in raphe serotonin biosynthesis, and polymorphisms of TPH2 are implicated in vulnerability to psychiatric disorders. Dynamic transcription regulation of TPH2 may underlie differences in vulnerability. We identified a transcription element in the TPH2 promoter that resembles the binding motif for RE-1 silencer of transcription (REST; also known as NRSF) transcription factor. REST limits tissue expression of non-neuronal genes through a canonical 21-bp motif called the NRSE (neuron-restrictive silencing element). The NRSE in TPH2 is a novel bipartite variant interrupted by a 6-base insertion. We confirmed that this bipartite NRSE permits transcriptional repression by REST identical to canonical NRSE in rat C6-glioma cells. Synthetic permutations of the motif revealed considerable flexibility in the juxtaposition of the two halves of bipartite NRSE. Computational analysis revealed many bipartite NRSE variants conserved between mouse and human genomes. A subgroup of these was found to bind REST by chromatin immunoprecipitation. Messenger RNAs for TPH2 and potassium channel H6, another gene with a bipartite NRSE, were up-regulated by dominant-negative REST in C6-glioma cells. These findings, which indicate that TPH2 expression is part of the developmental program regulated by REST and suggest that many previously unrecognized genes may be regulated by REST through the novel motif, have implications for the mechanism of REST action.

Received for publication, April 24, 2006

^* * This work was supported by National Institutes of Health Grants MH063992 (to P. D. P.) and NS38698 (to D. L. T.). 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 Tables S1 and S2.

² Member of the Pritzker Neuropsychiatric Disorders Research Consortium.

¹ To whom correspondence should be addressed: Molecular and Behavioral Neuroscience Inst., University of Michigan Medical Center, 5053 BSRB, 109 Zina Pitcher Pl., Ann Arbor, MI 48109-2200. Tel.: 734-647-9862; Fax: 734-936-2690; E-mail: pdpatel{at}umich.edu.

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