Genetic evidence that HNF-1α–dependent transcriptional control of HNF-4α is essential for human pancreatic β cell function

Mutations in the genes encoding hepatocyte nuclear factor 4 (HNF-4) and HNF-1 impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4 is known to be an essential positive regulator of HNF-1. More recent data demonstrates that HNF-4 expression is dependent on HNF-1 in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1 to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4 promoter (P1). Here we report that the expression of HNF-4 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-1 binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1, and consequently in reduced HNF-1-dependent activation. These findings provide genetic evidence that HNF-1 serves as an upstream regulator of HNF-4 and interacts directly with the P2 promoter in human pancreatic cells. Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function.