title: Long range regulation of human FXN gene expression.
abstract: BACKGROUND
  Friedreich ataxia (FRDA) is the most common form of hereditary ataxia characterized by the presence of a GAA trinucleotide repeat expansion within the first intron of the FXN gene. The expansion inhibits FXN gene expression resulting in an insufficiency of frataxin protein.
  
  
  RESULTS
  In this study, computational analyses were performed on the 21.3 kb region upstream of exon 1 of the human FXN gene and orthologs from other species in order to identify conserved non-coding DNA sequences with potential regulatory functions. The conserved non-coding regions identified were individually analyzed in two complementing assay systems, a conventional luciferase reporter system and a novel Bacterial Artificial Chromosome (BAC)-based genomic reporter. The BAC system allows the evaluation of gene expression to be made in the context of its entire genomic locus and preserves the normal location and spacing of many regulatory elements which may be positioned over large distances from the initiation codon of the gene.
  
  
  CONCLUSIONS
  The two approaches were used to identify a region of 17 bp located approximately 4.9 kb upstream of the first exon of the FXN gene that plays an important role in FXN gene expression. Modulation of FXN gene expression was found to be mediated by the action of the Oct-1 transcription factor at this site. A better understanding of cis-acting regulatory elements that control FXN gene expression has the potential to develop new strategies for the upregulation of the FXN gene as a therapy for FRDA.
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Novita
authors.initials: N
authors.lastname: Puspasari
authors.forename: Simone M
authors.initials: SM
authors.lastname: Rowley
authors.forename: Lavinia
authors.initials: L
authors.lastname: Gordon
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
authors.forename: Panos A
authors.initials: PA
authors.lastname: Ioannou
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Sarsero
mesh_terms: D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D019295:Computational Biology; D017124:Conserved Sequence / Q000235:genetics; D004247:DNA / Q000235:genetics; D021901:DNA, Intergenic; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D000096923:Frataxin
chemical_list: D004247:DNA; D021901:DNA, Intergenic; D033862:Iron-Binding Proteins; D050811:Octamer Transcription Factor-1; D000096923:Frataxin