AI Article Synopsis
- Friedreich ataxia is caused by an expanded GAA repeat in the FXN gene, leading to the silencing of the FXN promoter, which is observed in various cell types.
- In a humanized mouse model, YG8sR, researchers found a significant deficiency in FXN transcript levels compared to a control mouse, indicating that transcriptional initiation is impaired both upstream and downstream of the GAA repeat.
- This deficiency in transcriptional initiation is consistent across different tissues, suggesting that the mechanism of FXN promoter silencing is widespread, affecting both neuronal and non-neuronal cells.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579136 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138437 | PLOS |
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