Figure 5

Diagrammatic representation of an epigenetic model for Friedreich ataxia (FRDA). Not shown to scale. Unaffected alleles are aberrantly methylated in the region flanking the repeat. Nonetheless, the 5' end of the gene is associated with histones that are enriched for marks of active chromatin. In particular, acetylation of histone H3 and H4 is high. The net result is that the chromatin is open and permissive for transcription. Transcription factors including serum response factor (SRF), activator protein 2 (AP2) [73] and CCCTC-binding factor (CTCF) [25] associate with the 5' end of the gene. An early growth response protein 3 (EGR3)-like factor binds to the 5' end of intron 1 [73] and an E-box binding protein [48] bind to the region immediately upstream of the repeat. Under these conditions transcription initiation and elongation takes place normally. In contrast, FRDA alleles become associated with histones that are hypoacetylated and show more extensive DNA methylation in the region flanking the repeat. The net effect of these and other histone changes is the formation of a compact chromatin configuration. This reduces binding of transcription factors and both frataxin (FXN) transcription initiation and elongation are reduced. Loss of CTCF binding is correlated with an increase in the amount of FXN antisense transcript-1 (FAST-1) RNA that is transcribed antisense to FXN, but how this relates to silencing is unclear. TSS: transcription start site.