HNF1α is involved in tissue-specific regulation of CFTR gene expression

Nathalie Mouchel, Sytse A. Henstra, Victoria A. McCarthy, Sarah H. Williams, Marios Phylactides, Ann Harris*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

The CFTR (cystic fibrosis transmembrane conductance regulator) gene shows a complex pattern of expression with tissue-specific and temporal regulation. However, the genetic elements and transcription factors that control CFTR expression are largely unidentified. The CFTR promoter does not confer tissue specificity on gene expression, suggesting that there are regulatory elements outside the upstream region. Analysis of potential regulatory elements defined as DNase 1-hypersensitive sites within introns of the gene revealed multiple predicted binding sites for the HNF1α (hepatocyte nuclear factor 1α) transcription factor. HNF1α, which is expressed in many of the same epithelial cell types as CFTR and shows similar differentiation-dependent changes in gene expression, bound to these sites in vitro. Overexpression of heterologous HNF1α augmented CFTR transcription in vivo. In contrast, antisense inhibition of HNF1α transcription decreased the CFTR mRNA levels. Hnf1α knockout mice showed lower levels of CFTR mRNA in their small intestine in comparison with wild-type mice. This is the first report of a transcription factor, which confers tissue specificity on the expression of this important disease-associated gene.

Original languageEnglish (US)
Pages (from-to)909-918
Number of pages10
JournalBiochemical Journal
Volume378
Issue number3
DOIs
StatePublished - Mar 15 2004

Keywords

  • CFTR (cystic fibrosis transmembrane conductance regulator)
  • HNF1α (hepatocyte nuclear factor 1α)
  • Intronic regulatory elements

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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