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J. Biol. Chem., Vol. 278, Issue 52, 53082-53089, December 26, 2003

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Critical Role of the Transcriptional Repressor Neuron-restrictive Silencer Factor in the Specific Control of Connexin36 in Insulin-producing Cell Lines^*

David Martin, Thomas Tawadros, Laure Meylan, Amar Abderrahmani, Daniele F. Condorelli, Gérard Waeber, and Jacques-Antoine Haefliger

From the Department of Internal Medicine, University Hospital, CHUV-1011 Lausanne, Switzerland and the Department of Chemical Sciences, University of Catania, 95125 Catania, Italy

Connexin36 (Cx36) is specifically expressed in neurons and in pancreatic -cells. Cx36 functions as a critical regulator of insulin secretion and content in -cells. In order to identify the molecular mechanisms that control the -cell expression of Cx36, we initiated the characterization of the human 5' regulatory region of the CX36 gene. A 2043-bp fragment of the human CX36 promoter was identified from a human BAC library and fused to a luciferase reporter gene. This promoter region was sufficient to confer specific expression to the reporter gene in insulin-secreting cell lines. Within this 5' regulatory region, a putative neuron-restrictive silencer element conserved between rodent and human species was recognized and binds the neuron-restrictive silencing factor (NRSF/REST). This factor is not expressed in insulin-secreting cells and neurons; it functions as a potent repressor through the recruitment of histone deacetylase to the promoter of neuronal genes. The NRSF-mediated repression of Cx36 in HeLa cells was abolished by trichostatin A, confirming the functional importance of histone deacetylase activity. Ectopic expression, by viral gene transfer, of NRSF/REST in different insulin-secreting -cell lines induced a marked reduction in Cx36 mRNA and protein content. Moreover, mutations in the Cx36 neuron-restrictive silencer element relieved the low transcriptional activity of the human CX36 promoter observed in HeLa cells and in INS-1 cells expressing NRSF/REST. The data showed that cx36 gene expression in insulin-producing -cell lines is strictly controlled by the transcriptional repressor NRSF/REST indicating that Cx36 participates to the neuronal phenotype of the pancreatic -cells.

Received for publication, June 27, 2003 , and in revised form, September 26, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY341000.

^* This work was supported by Swiss National Science Foundation Grants 31-068036.02 (to J.-A. H.) and 32-66892.01 (to G. W.), the Juvenile Diabetes Research Foundation Grant 1-2001-555, the Placide Nicod and the Octav and Marcella Botnar Foundations (to G. W. and J.-A. H.), and by Telethon Foundation Grant E. 1283 (Italy) (to D. F. C.). 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.

To whom correspondence should be addressed: Dept. of Internal Medicine, Laboratory of Molecular Biology 19-135S, University Hospital, CHUV-1011 Lausanne, Switzerland. Tel.: 41-21-314-09-26; Fax: 41-21-314-09-68; E-mail: jhaeflig{at}chuv.hospvd.ch.

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