Genetic evidence that HNF-1 alpha-dependent transcriptional control of HNF-4 alpha is essential for human pancreatic beta cell function
Abstract
Mutations in the genes encoding hepatocyte nuclear factor 4alpha (HNF-4alpha) and HNF-1alpha impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4alpha is known to be an essential positive regulator of HNF-1alpha.
More recent data demonstrates that HNF-4alpha expression is dependent on HNF-1alpha. in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1alpha to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4alpha promoter (P1).
Here we report that the expression of HNF-4alpha in human islets and exocrine cells is primarily mediated by the P2 promoter. Furthermore, we describe a G --> A mutation in a conserved nucleotide position of the HNF-1alpha binding site of the P2 promoter, which cosegregates with MODY.
The mutation results in decreased affinity for HNF-1alpha., and consequently in reduced HNF-1alpha-dependent activation. These findings provide genetic evidence that HNF-1alpha serves as an upstream regulator of HNF-4alpha. and interacts directly with the P2 promoter in human pancreatic cells.
Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function