Objective: To investigate if DNA hypermethylation of the abnormal FXN gene in Friedreich ataxia is present in disease-relevant tissues and if it is tissue-, repeat-, and age-dependent.

Background: Friedreich ataxia is a progressive sensory ataxia caused by a GAA trinucleotide repeat expansion in intron 1 of the FXN gene. The expanded repeat produces repressive heterochromatin that results in transcriptional silencing of the FXN gene. Clinical manifestations, such as ataxia and cardiomyopathy are positively correlated with the size of the expanded repeat. Despite the silencing, the FXN promoter and surrounding CpG island (CGI) remain unmethylated. However, the FXN CGI shore is hypermethylated in Friedreich ataxia, which is a known cause of transcriptional silencing.

Methods: DNA from various tissues from the humanized mouse model of Friedreich ataxia, both young (1 mo) and old (12 mo) containing 8, 200, and 450 GAA repeats, were analyzed for DNA methylation using bisulfite deep sequencing.

Results: Hypermethylation of the CGI shore was noted in all disease-relevant tissues in both the GAA-200 and GAA-450 mice. Methylation was dependent on the repeat length. Strikingly, FXN CGI shore methylation decreased over time, and this was most pronounced in the heart of GAA-200 mice.

Conclusions: FXN DNA methylation reduces throughout life in the presence of a short expanded allele, and may explain the lower prevalence and severity of cardiomyopathy in Friedreich ataxia patients with short repeats.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/epigenetic-silencing-in-the-humanized-mouse-model-of-friedreich-ataxia/