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Molecular and Cellular Biology, August 2005, p. 7069-7077, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.7069-7077.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transcriptional Networks in the Liver: Hepatocyte Nuclear Factor 6 Function Is Largely Independent of Foxa2

Nir E. Rubins,1,3 Joshua R. Friedman,1,2,3 Phillip P. Le,1,3 Liping Zhang,1,3 John Brestelli,1,3 and Klaus H. Kaestner1,3*

Department of Genetics,1 Department of Pediatrics,2 Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, 570 CRB, 415 Curie Blvd., Philadelphia, Pennsylvania 191043

Received 15 March 2005/ Returned for modification 15 April 2005/ Accepted 18 May 2005

A complex network of hepatocyte nuclear transcription factors, including HNF6 and Foxa2, regulates the expression of liver-specific genes. The current model, based on in vitro studies, suggests that HNF6 and Foxa2 interact physically. This interaction is thought to synergistically stimulate Foxa2-dependent transcription through the recruitment of p300/CBP by HNF6 and to inhibit HNF6-mediated transcription due to the interference of Foxa2 with DNA binding by HNF6. To test this model in vivo, we utilized hepatocyte-specific gene ablation to study the binding of HNF6 to its targets in the absence of Foxa2. Chromatin immunoprecipitation using anti-HNF6 antibodies was performed on chromatin isolated from Foxa2loxP/loxP Alfp.Cre and control mouse livers, and HNF6 binding to its target, Glut2, was determined by quantitative PCR. In contrast to the current model, we found no significant difference in HNF6 occupancy at the Glut2 promoter between Foxa2-deficient and control livers. In order to evaluate the Foxa2/HNF6 interaction model on a global scale, we performed a location analysis using a microarray with 7,000 mouse promoter fragments. Again, we found no evidence that HNF6 binding to its targets in chromatin is reduced in the presence of Foxa2. We also examined the mRNA levels of HNF6 targets in the liver using a cDNA array and found that their expression was similar in Foxa2-deficient and control mice. Overall, our studies demonstrate that HNF6 binds to and regulates its target promoters in vivo in the presence and absence of Foxa2.

* Corresponding author. Mailing address: Department of Genetics, University of Pennsylvania, 570 CRB, 415 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-8759. Fax: (215) 573-5892. E-mail: kaestner{at}mail.med.upenn.edu.

Molecular and Cellular Biology, August 2005, p. 7069-7077, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.7069-7077.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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