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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

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).
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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).

Mentions: Although the exact mechanism by which the GAA repeat expansion leads to decreased frataxin expression is not known, two hypotheses have been proposed (Figure 1). Firstly, evidence from in vitro and cell transfection studies suggests that the GAA repeat expansion may adopt abnormal non-B DNA structures (triplexes or “sticky DNA”) or DNA•RNA hybrid structures (R-loops), which impede the process of RNA polymerase II and thus reduce FXN gene transcription (Grabczyk et al., 2007; Wells, 2008). Secondly, there is evidence that GAA repeat expansions can produce heterochromatin-mediated gene silencing effects (Saveliev et al., 2003). Consistent with the latter hypothesis, several FRDA disease-related epigenetic changes have been identified in the immediate vicinity of the expanded GAA repeats of the FXN gene and these changes will be discussed further within this review.


Epigenetic-based therapies for Friedreich ataxia.

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

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

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

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).
Mentions: Although the exact mechanism by which the GAA repeat expansion leads to decreased frataxin expression is not known, two hypotheses have been proposed (Figure 1). Firstly, evidence from in vitro and cell transfection studies suggests that the GAA repeat expansion may adopt abnormal non-B DNA structures (triplexes or “sticky DNA”) or DNA•RNA hybrid structures (R-loops), which impede the process of RNA polymerase II and thus reduce FXN gene transcription (Grabczyk et al., 2007; Wells, 2008). Secondly, there is evidence that GAA repeat expansions can produce heterochromatin-mediated gene silencing effects (Saveliev et al., 2003). Consistent with the latter hypothesis, several FRDA disease-related epigenetic changes have been identified in the immediate vicinity of the expanded GAA repeats of the FXN gene and these changes will be discussed further within this review.

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