Epigenetic-based therapies for Friedreich ataxia

Abstract

Friedreich ataxia (FRDA) is a lethal autosomal recessive neurodegenerative disorder caused primarily by a homozygous GAA repeat expansion mutation within the first intron of the FXN gene, leading to inhibition of FXN transcription and thus reduced frataxin protein expression. Recent studies have shown that epigenetic marks, comprising chemical modifications of DNA and histones, are associated with FXN gene silencing. Such epigenetic marks can be reversed, making them suitable targets for epigenetic-based therapy. Furthermore, since FRDA is caused by insufficient, but functional, frataxin protein, epigenetic-based transcriptional re-activation of the FXN gene is an attractive therapeutic option. In this review we summarize our current understanding of the epigenetic basis of FXN gene silencing and we discuss current epigenetic-based FRDA therapeutic strategies.

Keywords: DNA demethylation; FRDA; FXN; Friedreich ataxia; GAA repeat; HDAC inhibitor; HMTase inhibitor; frataxin.

Figure 1

Models of FXN gene silencing in FRDA. (A) Unaffected individuals, who carry up to 43 GAA•TTC repeats, contain active histone marks of gene transcription initiation and elongation at the FXN promoter and intron 1 regions. (B) In FRDA patients, the presence of large GAA•TTC repeat expansion leads to FXN gene silencing by two potential mechanisms: (i) the GAA•TTC repeat may adopt abnormal non-B DNA structures (triplexes) or DNA•RNA hybrid structures (R loops), which impede the process of RNA polymerase and thus reduce FXN gene transcription, (ii) increased levels of DNA methylation and HP1 and significant enrichment of repressive histone marks at the FXN gene trigger heterochromatin formation that may lead to more pronounced FXN gene silencing. This image was adapted from Festenstein (2006); Wells (2008); Chan et al. (2013).

Figure 2

The position of DNA methylation, hydroxymethylation, and CTCF binding sites within the FXN gene. (A) Unaffected: normal-sized GAA repeat (B) FRDA: GAA repeat expansion. Gray boxes represent regions of disease-associated DNA methylation and hydroxymethylation. Arrow marks represent the directions and levels of transcription for FXN and FAST-1. Blue bars represent exons of the FXN gene. Red triangles indicate GAA repeats within intron 1 of the FXN gene.

Figure 3

Potential epigenetic-based therapies for FRDA. Large GAA•TTC repeats in FRDA patients are associated with heterochromatin mediated FXN gene silencing. The use of specific HDAC inhibitors, HDM activators, HAT activators, HMTase inhibitors, or agRNA activation may reverse the heterochromatin to a more open chromatin structure, and may thus lead to active FXN gene transcription. This image was adapted from Festenstein (2006); Chan et al. (2013).