title: Reversal of epigenetic promoter silencing in Friedreich ataxia by a class I histone deacetylase inhibitor.
abstract: Friedreich ataxia, the most prevalent inherited ataxia, is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene. Repressive chromatin spreads from the expanded GAA triplet-repeat sequence to cause epigenetic silencing of the FXN promoter via altered nucleosomal positioning and reduced chromatin accessibility. Indeed, deficient transcriptional initiation is the predominant cause of transcriptional deficiency in Friedreich ataxia. Treatment with 109, a class I histone deacetylase (HDAC) inhibitor, resulted in increased level of FXN transcript both upstream and downstream of the expanded GAA triplet-repeat sequence, without any change in transcript stability, suggesting that it acts via improvement of transcriptional initiation. Quantitative analysis of transcriptional initiation via metabolic labeling of nascent transcripts in patient-derived cells revealed a >3-fold increase (P < 0.05) in FXN promoter function. A concomitant 3-fold improvement (P < 0.001) in FXN promoter structure and chromatin accessibility was observed via Nucleosome Occupancy and Methylome Sequencing, a high-resolution in vivo footprint assay for detecting nucleosome occupancy in individual chromatin fibers. No such improvement in FXN promoter function or structure was observed upon treatment with a chemically-related inactive compound (966). Thus epigenetic promoter silencing in Friedreich ataxia is reversible, and the results implicate class I HDACs in repeat-mediated promoter silencing.
authors.affiliation: Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, USA.
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, USA.
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, USA.
authors.forename: Whitney N
authors.initials: WN
authors.lastname: Costello
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Anderson
authors.affiliation: Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, USA Department of Biostatistics & Epidemiology, University of Oklahoma College of Public Health, Oklahoma City, OK 73104, USA Sanjay-Bidichandani@ouhsc.edu.
authors.forename: Sanjay I
authors.initials: SI
authors.lastname: Bidichandani
mesh_terms: D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005621:Friedreich Ataxia / Q000235:genetics*; D020868:Gene Silencing / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics; D009707:Nucleosomes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020871:RNA Stability; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion; D000096923:Frataxin
chemical_list: D056572:Histone Deacetylase Inhibitors; D033862:Iron-Binding Proteins; D009707:Nucleosomes; D000096923:Frataxin