Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function

Research output: Contribution to journalJournal articleResearchpeer-review

Sara K Hansen, Marcelina Párrizas, Maria L Jensen, Stepanka Pruhova, Jakob Ek, Sylvia F Boj, Anders Johansen, Miguel A Maestro, Francisca Rivera, Hans Eiberg, Michal Andel, Jan Lebl, Oluf Pedersen, Jorge Ferrer, Torben Hansen

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.
Original languageEnglish
JournalJournal of Clinical Investigation
Volume110
Issue number6
Pages (from-to)827-33
Number of pages7
ISSN0021-9738
DOIs
Publication statusPublished - 2002

    Research areas

  • Adolescent, Adult, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Child, Child, Preschool, DNA-Binding Proteins, Diabetes Mellitus, Type 2, Female, Genes, Reporter, Hepatocyte Nuclear Factor 1, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 1-beta, Hepatocyte Nuclear Factor 4, Humans, Infant, Islets of Langerhans, Male, Mutation, Nuclear Proteins, Pedigree, Phosphoproteins, Promoter Regions, Genetic, Receptors, Glucocorticoid, Transcription Factors, Transcription, Genetic

ID: 38457884