DNA polymorphisms in potential regulatory elements of the CFTR gene alter transcription factor binding

Hum Genet. 2002 Jul;111(1):66-74. doi: 10.1007/s00439-002-0737-z. Epub 2002 Jun 6.

Abstract

Over one thousand mutations have been identified to date in the cystic fibrosis transmembrane conductance regulator gene ( CFTR); however, about 5-10% of mutations remain undefined. It is likely that some of these undefined mutations occur within regulatory elements for the CFTR gene. Tissue-specific regulatory elements for CFTR are located outside the basal promoter region and may be associated with DNase I hypersensitive sites (DHS). We previously described a DHS at +15.6 kb 3' to the CFTR gene, which showed tissue specificity in vivo and was evaluated as a candidate regulatory element for CFTR. Polymorphisms in regulatory elements may have a significant effect on their activity and hence on the levels of gene expression. Two C-->T polymorphisms were identified within the +15.6 kb region that occurred on both cystic fibrosis (CF) and non-CF alleles. Both of the polymorphisms altered DNA-protein binding, as shown by electrophoretic mobility shift assays (EMSA). These changes in transcription factor binding at a putative regulatory region could influence CFTR gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Binding Sites
  • Binding, Competitive
  • COUP Transcription Factors
  • Case-Control Studies
  • Cells, Cultured
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • DNA Footprinting
  • DNA Primers / chemistry
  • DNA-Binding Proteins / metabolism
  • Deoxyribonuclease I
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation
  • Hepatocyte Nuclear Factor 4
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Oligonucleotides / metabolism
  • Phosphoproteins / metabolism
  • Polymerase Chain Reaction
  • Polymorphism, Genetic*
  • Polymorphism, Single-Stranded Conformational
  • Promoter Regions, Genetic / genetics*
  • Protein Binding
  • Receptors, Steroid*
  • Regulatory Sequences, Nucleic Acid
  • Transcription Factors / metabolism
  • Transcription, Genetic

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CFTR protein, human
  • COUP Transcription Factors
  • DNA Primers
  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 4
  • MLX protein, human
  • Oligonucleotides
  • Phosphoproteins
  • Receptors, Steroid
  • Transcription Factors
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Deoxyribonuclease I