Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Genetic evidence that HNF-1α–dependent transcriptional control of HNF-4α is essential for human pancreatic β cell function
Sara K. Hansen, … , Jorge Ferrer, Torben Hansen
Sara K. Hansen, … , Jorge Ferrer, Torben Hansen
Published September 15, 2002
Citation Information: J Clin Invest. 2002;110(6):827-833. https://doi.org/10.1172/JCI15085.
View: Text | PDF
Article Genetics

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

  • Text
  • PDF
Abstract

Mutations in the genes encoding hepatocyte nuclear factor 4α (HNF-4α) and HNF-1α impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4α is known to be an essential positive regulator of HNF-1α. More recent data demonstrates that HNF-4α expression is dependent on HNF-1α in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1α to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4α promoter (P1). Here we report that the expression of HNF-4α 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-1α binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1α, and consequently in reduced HNF-1α–dependent activation. These findings provide genetic evidence that HNF-1α serves as an upstream regulator of HNF-4α and interacts directly with the P2 promoter in human pancreatic cells. Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function.

Authors

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

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Expression of HNF-4α transcripts in human tissues. (a) Schematic represe...
Expression of HNF-4α transcripts in human tissues. (a) Schematic representation of possible combinations of HNF-4α splice variations (adapted from ref. 27). Numbers indicate exons. Arrows indicate oligonucleotides used for RT-PCR. (b) RT-PCR analysis of HNF-4α exon 1A (transcribed from the P1 promoter) versus exon 1D (transcribed from the P2 promoter) in pancreatic tissues and liver. β-actin is used as internal control for the RT-PCR procedure. Only one band is amplified using primers designed to amplify HNF-4α exon 1A+2, indicating that transcripts originating in either tissue do not contain exon 1B. (c) RT-PCR analysis of HNF-4α 3′ end splice variations in human islets and liver. The 8F+10R primer set amplifies two fragments containing or lacking an extended exon 9 (9+) insertion. According to these results, liver contains predominantly HNF-4α1, -4α2, and -4α3 transcripts, whereas pancreatic cells contain HNF-4α7, -4α8, and -4α9 variants.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts