Friedreich ataxia (FRDA) is the most commonly inherited ataxia. It is recessively inherited, and caused by an expansion of the GAA TTC repeat, present in the intron 1 of the frataxin FXN gene. The expanded alleles produce less mature mRNA, although the repeats could alter the expression in other ways, as occurs with the centromeric tandem repeats that are normaly silenced. Since this control is probably by means of alteration of epigenetic marks, these chromatin alterations were evaluated for the FXN gene. First, analysis of the region of intron 1 between exon 1 and the FXN repeat was found to contain three interspersed repeated elements. Bisulfite sequencing of this region showed that most CpGs were methylated both on affected and unaffected individuals, but methylation was more extensive in the first group. Patients with FRDA also had elevated levels of H3K9me2, a mark of chromatin compaction, that correlated with low levels of FXN mRNA. This data support the idea of a epigenetic mechanism responsible for the low expression of FXN.
epigenetics
Greene E. et al. 2007. Nucleic Acids Res 35(10):3383-90
How could the long FXN-repeat tracts in patient cells generate transcriptionally silent chromatin? One possibility is that this process involves small double-stranded RNAs (dsRNAs) that target the transcriptional silencing machinery to homologous regions of the genome. [...] Repeat-mediated heterochromatin formation is seen in two other Repeat Expansion diseases: Fragile X syndrome and the congenital form of Myotonic Dystrophy type 1. Thus repeat-mediated transcriptional silencing may provide a common thread linking these diseases where the repeat is transcribed but not translated.
epigenetics
