Journal article
FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia
PloS one, Vol.10(9), pp.e0138437-e0138437
09/22/2015
DOI: 10.1371/journal.pone.0138437
PMCID: PMC4579136
PMID: 26393353
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.
Methodology / Principal Findings
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.
Conclusions / Significance
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.
Details
- Title: Subtitle
- FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia
- Creators
- Yogesh K. Chutake - University of OklahomaWhitney N. Costello - University of OklahomaChristina C. Lam - University of OklahomaAniruddha C. Parikh - University of OklahomaTamara T. Hughes - University of OklahomaMichael G. Michalopulos - University of OklahomaMark A. Pook - Brunel University LondonSanjay I. Bidichandani - University of Oklahoma
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.10(9), pp.e0138437-e0138437
- Publisher
- Public Library Science
- DOI
- 10.1371/journal.pone.0138437
- PMID
- 26393353
- PMCID
- PMC4579136
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Number of pages
- 12
- Grant note
- R01NS072418 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) U54GM104938 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) American College of Medical Genetics Foundation Million Dollar Bike Ride Grant Program of the Orphan Disease Center at University of Pennsylvania Muscular Dystrophy Association OUHSC R01 NS072418 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 09/22/2015
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics
- Record Identifier
- 9984702940402771
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