title: HNF1alpha is involved in tissue-specific regulation of CFTR gene expression.
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 HNF1alpha (hepatocyte nuclear factor 1alpha) transcription factor. HNF1alpha, 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 HNF1alpha augmented CFTR transcription in vivo. In contrast, antisense inhibition of HNF1 alpha transcription decreased the CFTR mRNA levels. Hnf1 alpha 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.
authors.affiliation: Paediatric Molecular Genetics, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mouchel
authors.forename: Sytse A
authors.initials: SA
authors.lastname: Henstra
authors.forename: Victoria A
authors.initials: VA
authors.lastname: McCarthy
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Williams
authors.forename: Marios
authors.initials: M
authors.lastname: Phylactides
authors.forename: Ann
authors.initials: A
authors.lastname: Harris
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D003850:Deoxyribonuclease I / Q000378:metabolism; D005786:Gene Expression Regulation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D007438:Introns; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D009928:Organ Specificity; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: C505032:CFTR protein, human; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D009687:Nuclear Proteins; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D003850:Deoxyribonuclease I