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

      The Journal of clinical investigation

      Adolescent, Adult, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Child, Child, Preschool, DNA-Binding Proteins, genetics, metabolism, 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, physiology, Male, Mutation, Nuclear Proteins, Pedigree, Phosphoproteins, Promoter Regions, Genetic, Receptors, Glucocorticoid, Transcription Factors, Transcription, Genetic

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          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.

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          Journal
          12235114
          151122
          10.1172/JCI15085

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