The MODY1 gene for hepatocyte nuclear factor 4alpha and a feedback loop control COUP-TFII expression in pancreatic beta cells.
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 4alpha (HNF4alpha) 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 HNF4alpha activation of a reporter plasmid containing the COUP-TFII gene promoter region in transfected pancreatic beta cells. The stable association of the endogenous HNF4alpha 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 HNF4alpha transactivation of COUP-TFII. The dominant negative suppression of HNF4alpha function decreased endogenous COUP-TFII expression, and the specific inactivation of COUP-TFII by small interfering RNA caused HNF4alpha mRNA levels in 832/13 INS-1 cells to decrease. This positive regulation of HNF4alpha by COUP-TFII was confirmed by the adenovirus-mediated overexpression of human COUP-TFII (hCOUP-TFII), which increased HNF4alpha 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 HNF4alpha/maturity-onset diabetes of the young 1 (MODY1) transcription factor network operating in beta cells.
Perilhou
Anaïs
A
Department of Endocrinology, Metabolism and Cancer, Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris, France.
Tourrel-Cuzin
Cécile
C
Zhang
Pili
P
Kharroubi
Ilham
I
Wang
Haiyan
H
Fauveau
Véronique
V
Scott
Donald K
DK
Wollheim
Claes B
CB
Vasseur-Cognet
Mireille
M
D000818:Animals; D051837:COUP Transcription Factor II / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D053263:Gene Regulatory Networks; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011401:Promoter Regions, Genetic; D051381:Rats; D015533:Transcriptional Activation
D051837:COUP Transcription Factor II; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; C497587:Nr2f2 protein, mouse; C497588:Nr2f2 protein, rat; C095569:NR2F2 protein, human