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Mol. Cell. Biol. doi:10.1128/MCB.01191-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The MODY1 gene HNF4 and a feedback loop control COUP-TFII expression in pancreatic beta cells

Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Department of Endocrinology, Metabolism and Cancer Paris, France; Inserm, U567, Paris, France; Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; PRBD-Metabolic diseases, Hoffmann-La Roche, Basel, Switzerland; Department of Cell Physiology and Metabolism, University Medical Centre, 1211 Geneva 4, Switzerland

^* To whom correspondence should be addressed. Email: vasseur{at}cochin.inserm.fr.

	Abstract

Pancreatic islet beta cell differentiation and function are dependent upon a group of transcription factors that maintain the expression of key genes and suppress others. Knockout mice with heterozygous deletion of the Chicken Ovalbumin Upstream Promoter- Transcription Factor II (COUP-TFII) gene or complete disruption of the Hepatocyte Nuclear Factor 4 (HNF4) gene in pancreatic beta cells have similar insulin secretion defects leading us to hypothesize that there is transcriptional cross-talk between these two nuclear receptors. Here we show specific HNF4 activation of a reporter plasmid containing the COUP-TFII promoter region in transfected pancreatic beta cells. A stable association of the endogenous HNF4 with a region of the COUP-TFII gene promoter that contains a direct repeat 1 (DR-1) binding site was revealed by chromatin immunoprecipitation. Mutation experiments showed that this DR-1 site is essential for HNF4 transactivation of COUP-TFII. Dominant negative suppression of HNF4 function decreased endogenous COUP-TFII expression and specific inactivation of COUP-TFII by short interfering (si)RNA caused HNF4 mRNA levels to decrease in 832/13 INS-1 cells. This positive regulation of HNF4 by COUP-TFII was confirmed by adenoviral overexpression of human (h)COUP-TFII which increased HNF4 mRNA in 832/13 INS-1 cells and in mouse pancreatic islets. Finally, hCOUP-TFII overexpression showed that there is direct COUP-TFII autorepression as COUP-TFII occupies the proximal DR-1 binding site of its own gene in vivo. Therefore COUP-TFII could contribute to the control of insulin secretion through the complex HNF4/maturity-onset diabetes of the young 1 (MODY1) transcription factor network operating in beta cells.