FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia

Chutake YK, Costello WN, Lam CC, Parikh AC, Hughes TT, Michalopulos MG, Mark A. Pook, Sanjay I. Bidichandani. (2015) FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia. PLoS ONE 10(9): e0138437. doi:10.1371/journal.pone.0138437

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Our results indicate that FXN transcriptional deficiency in the YG8sR humanized mouse model of FRDA is caused by deficient transcriptional initiation as a result of promoter silencing. While this mechanism has previously been noted in patient-derived lymphoblastoid cell lines, our present data provide supportive evidence for the existence of this mechanism of transcriptional deficiency in fibroblasts and in multiple tissues. Our data also suggest that the mechanism underlying FXN transcriptional deficiency in FRDA is unlikely to be tissue-specific.

Our data indicate that the YG8sR humanized mouse is a reasonable model for investigating the molecular mechanism(s) underlying repeat-mediated promoter silencing in FRDA. The YG8sR mouse model would also be useful for testing drugs that are designed to reverse the transcriptional initiation defect caused by promoter silencing in FRDA, such as the 2-aminobenzamide derived histone deacetylase inhibitors.


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