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

Abstract

Hepatic nuclear factor (HNF)-4alpha and HNF-1alpha are key endodermal transcriptional regulators that physically and functionally interact. HNF-4alpha and HNF-1alpha 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-4alpha increased HNF-1alpha Fabp1 promoter occupancy during cooperative transcriptional activation. The HNF4 P2 promoter contains a HNF-1 but not HNF-4 binding site, and HNF-4alpha suppressed HNF-1alpha HNF4 P2 activation and decreased promoter HNF-1alpha occupancy. The apolipoprotein C III (APOC3) promoter contains a HNF-4 but not HNF-1 binding site, and HNF-1alpha suppressed HNF-4alpha APOC3 activation and decreased HNF-4alpha promoter occupancy. Maturity onset diabetes of the young (MODY) as well as defects in hepatic lipid metabolism result from mutations in either HNF-4alpha or HNF-1alpha. We found that MODY missense mutant R127W HNF-4alpha retained wild-type individual Fabp1 activation and bound to HNF-1alpha better than wild-type HNF-4alpha, yet did not cooperate with HNF-1alpha or increase HNF-1alpha Fabp1 promoter occupancy. The R127W mutant was also defective in both suppressing HNF-1alpha activation of HNF4 P2 and decreasing HNF-1alpha promoter occupancy. The HNF-1alpha R131Q MODY mutant also retained wild-type Fabp1 activation and bound to HNF-4alpha as well as the wild type but was defective in both suppressing HNF-4alpha APOC3 activation and decreasing HNF-4alpha promoter occupancy. These results suggest HNF-1alpha-HNF-4alpha functional interactions are accomplished by regulating factor promoter occupancy and that defective factor-factor interactions may contribute to the MODY phenotype.

• Authors: Christopher W Rowley, Lora J Staloch, Joyce K Divine, Sean P McCaul, Theodore C Simon
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 290 Issue 3 Pg. G466-75 (Mar 2006) ISSN: 0193-1857 [Print] United States
• PMID: 16223942 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• FABP1 protein, human
• Fatty Acid-Binding Proteins
• HNF4A protein, human
• Hepatocyte Nuclear Factor 1-alpha
• Hepatocyte Nuclear Factor 4

Topics

• Caco-2 Cells
• Diabetes Mellitus, Type 2 (genetics, physiopathology)
• Fatty Acid-Binding Proteins (genetics)
• HeLa Cells
• Hepatocyte Nuclear Factor 1-alpha (genetics, physiology)
• Hepatocyte Nuclear Factor 4 (genetics, physiology)
• Humans
• Mutation, Missense
• Promoter Regions, Genetic
• Transgenes (physiology)