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Molecular and Cellular Biology, July 2008, p. 4588-4597, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.01191-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The MODY1 Gene for Hepatocyte Nuclear Factor 4 and a Feedback Loop Control COUP-TFII Expression in Pancreatic Beta Cells

Department of Endocrinology, Metabolism and Cancer, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France,¹ INSERM, U567, Paris, France,² Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,³ PRBD-Metabolic Diseases, Hoffmann-La Roche, Basel, Switzerland,⁴ Department of Cell Physiology and Metabolism, University Medical Centre, 1211 Geneva 4, Switzerland⁵

Received 4 July 2007/ Returned for modification 2 August 2007/ Accepted 18 April 2008

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 the heterozygous deletion of the gene for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) or the complete disruption of the gene for hepatocyte nuclear factor 4 (HNF4) 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 demonstrate specific HNF4 activation of a reporter plasmid containing the COUP-TFII gene promoter region in transfected pancreatic beta cells. The 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. The dominant negative suppression of HNF4 function decreased endogenous COUP-TFII expression, and the specific inactivation of COUP-TFII by small interfering RNA caused HNF4 mRNA levels in 832/13 INS-1 cells to decrease. This positive regulation of HNF4 by COUP-TFII was confirmed by the adenovirus-mediated overexpression of human COUP-TFII (hCOUP-TFII), which increased HNF4 mRNA levels 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 may 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.

Published ahead of print on 12 May 2008.