title: FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia.
abstract: BACKGROUND
  Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues.
  The humanized mouse model of Friedreich ataxia (YG8sR), which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R). We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse.
  Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.
authors.affiliation: Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States of America.
authors.forename: Yogesh K
authors.initials: YK
authors.lastname: Chutake
authors.affiliation: Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States of America.
authors.forename: Whitney N
authors.initials: WN
authors.lastname: Costello
authors.affiliation: Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States of America.
authors.forename: Christina C
authors.initials: CC
authors.lastname: Lam
authors.affiliation: Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States of America.
authors.forename: Aniruddha C
authors.initials: AC
authors.lastname: Parikh
authors.affiliation: Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States of America.
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Hughes
authors.affiliation: Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Michalopulos
authors.affiliation: Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health & Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pook
authors.affiliation: Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States of America; Department of Biochemistry & Molecular Biology, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States of America.
authors.forename: Sanjay I
authors.initials: SI
authors.lastname: Bidichandani
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005621:Friedreich Ataxia / Q000235:genetics* / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D007438:Introns; D033862:Iron-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D018911:Trinucleotide Repeats; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D000096923:Frataxin