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LIVER AND BILIARY TRACT

Mechanisms of mutual functional interactions between HNF-4 and HNF-1 revealed by mutations that cause maturity onset diabetes of the young

²Division of Biology and Biomedical Sciences, and ¹Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri

Submitted 13 September 2005 ; accepted in final form 6 October 2005

Hepatic nuclear factor (HNF)-4 and HNF-1 are key endodermal transcriptional regulators that physically and functionally interact. HNF-4 and HNF-1 cooperatively activate genes with binding sites for both factors, whereas suppressive interactions occur at regulatory sequences with a binding site for only one factor. The liver fatty acid binding protein gene (Fabp1) has binding sites for both factors, and chromatin precipitation assays were utilized to demonstrate that HNF-4 increased HNF-1 Fabp1 promoter occupancy during cooperative transcriptional activation. The HNF4 P2 promoter contains a HNF-1 but not HNF-4 binding site, and HNF-4 suppressed HNF-1 HNF4 P2 activation and decreased promoter HNF-1 occupancy. The apolipoprotein C III (APOC3) promoter contains a HNF-4 but not HNF-1 binding site, and HNF-1 suppressed HNF-4 APOC3 activation and decreased HNF-4 promoter occupancy. Maturity onset diabetes of the young (MODY) as well as defects in hepatic lipid metabolism result from mutations in either HNF-4 or HNF-1. We found that MODY missense mutant R127W HNF-4 retained wild-type individual Fabp1 activation and bound to HNF-1 better than wild-type HNF-4, yet did not cooperate with HNF-1 or increase HNF-1 Fabp1 promoter occupancy. The R127W mutant was also defective in both suppressing HNF-1 activation of HNF4 P2 and decreasing HNF-1 promoter occupancy. The HNF-1 R131Q MODY mutant also retained wild-type Fabp1 activation and bound to HNF-4 as well as the wild type but was defective in both suppressing HNF-4 APOC3 activation and decreasing HNF-4 promoter occupancy. These results suggest HNF-1-HNF-4 functional interactions are accomplished by regulating factor promoter occupancy and that defective factor-factor interactions may contribute to the MODY phenotype.

transcription factor; hepatic nuclear factor-4; hepatic nuclear factor-1

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