Limits...
Epigenetic-based therapies for Friedreich ataxia.

Sandi C, Sandi M, Anjomani Virmouni S, Al-Mahdawi S, Pook MA - Front Genet (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London Uxbridge, UK.

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.

No MeSH data available.


Related in: MedlinePlus

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4042889&req=5

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.

Mentions: Initial investigations of DNA methylation within the FXN gene by Usdin and colleagues revealed hypermethylation of specific CpG sites upstream of the GAA repeat sequence in FRDA patient-derived lymphoblastoid cells compared to cells derived from unaffected individuals (Greene et al., 2007). In particular, three out of 15 CpG residues that span a 700 bp region upstream of the GAA repeat were found to be unmethylated, or sparsely methylated, in unaffected cells, but highly methylated in FRDA cells. Studies by our laboratory also revealed significantly increased DNA methylation at the same upstream GAA repeat region in FRDA patient autopsy brain, heart, and cerebellum tissues, with similar findings in tissues of FRDA YAC transgenic mice (Al-Mahdawi et al., 2008). Subsequently, a study of FRDA patient blood samples showed that the degree of DNA methylation at the FXN upstream GAA repeat region correlates with the length of the GAA repeats and inversely correlates with the age of disease onset (Castaldo et al., 2008). Furthermore, analysis of blood and buccal cells from a large cohort of FRDA patients showed that the level of DNA methylation in FRDA patients is significantly elevated in the same upstream GAA repeat region and inversely correlated with FXN expression levels (Evans-Galea et al., 2012). More recently, our laboratory has shown that, for at least one CpG site within the upstream GAA repeat region, the increased level of DNA methylation predominantly comprises 5hmC rather than 5mC (Al-Mahdawi et al., 2013). Thus, FRDA can now be grouped together with other TNR expansion diseases in which an association with DNA methylation and hydroxymethylation has been observed (Table 1, Figure 2).


Epigenetic-based therapies for Friedreich ataxia.

Sandi C, Sandi M, Anjomani Virmouni S, Al-Mahdawi S, Pook MA - Front Genet (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042889&req=5

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.
Mentions: Initial investigations of DNA methylation within the FXN gene by Usdin and colleagues revealed hypermethylation of specific CpG sites upstream of the GAA repeat sequence in FRDA patient-derived lymphoblastoid cells compared to cells derived from unaffected individuals (Greene et al., 2007). In particular, three out of 15 CpG residues that span a 700 bp region upstream of the GAA repeat were found to be unmethylated, or sparsely methylated, in unaffected cells, but highly methylated in FRDA cells. Studies by our laboratory also revealed significantly increased DNA methylation at the same upstream GAA repeat region in FRDA patient autopsy brain, heart, and cerebellum tissues, with similar findings in tissues of FRDA YAC transgenic mice (Al-Mahdawi et al., 2008). Subsequently, a study of FRDA patient blood samples showed that the degree of DNA methylation at the FXN upstream GAA repeat region correlates with the length of the GAA repeats and inversely correlates with the age of disease onset (Castaldo et al., 2008). Furthermore, analysis of blood and buccal cells from a large cohort of FRDA patients showed that the level of DNA methylation in FRDA patients is significantly elevated in the same upstream GAA repeat region and inversely correlated with FXN expression levels (Evans-Galea et al., 2012). More recently, our laboratory has shown that, for at least one CpG site within the upstream GAA repeat region, the increased level of DNA methylation predominantly comprises 5hmC rather than 5mC (Al-Mahdawi et al., 2013). Thus, FRDA can now be grouped together with other TNR expansion diseases in which an association with DNA methylation and hydroxymethylation has been observed (Table 1, Figure 2).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London Uxbridge, UK.

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.

No MeSH data available.


Related in: MedlinePlus