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Friedreich's ataxia--a case of aberrant transcription termination?

Butler JS, Napierala M - Transcription (2015)

Bottom Line: Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia.We propose a model of premature termination of FXN transcription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia.

View Article: PubMed Central - PubMed

Affiliation: a University of Alabama at Birmingham; Department of Biochemistry and Molecular Genetics ; UAB Stem Cell Institute ; Birmingham , AL USA.

ABSTRACT
Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia. We propose a model of premature termination of FXN transcription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia.

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Proposed model of R-loop induced aberrant transcription termination of the FXN gene at the expanded GAA repeats. (A) Transcription of FXN harboring short GAAs (depicted as a green line) in unaffected cells. (B) Transcriptional termination at the expanded GAA region (depicted as a red line) is initiated by formation of R-loops between the FXN mRNA and DNA template strand. R-loops can stimulate antisense transcription (either FAST1 or putative GAA-AS) at the GAA repeats. Recruitment of transcription factors to the GAAs can initiate synthesis of the antisense transcript at the repeat region. Bidirectional transcription of the expanded GAA•TTC sequences facilitates formation of a dsRNA between coding and non-coding strands, recruiting Ago/Dicer and histone methyltransferase (G9a), and leading to histone H3K9 methylation and HP1γ binding. Heterochromatin formation and appropriate sequence context (multiple PAS) result in recurrent, aberrant termination of RNA synthesis.
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f0001: Proposed model of R-loop induced aberrant transcription termination of the FXN gene at the expanded GAA repeats. (A) Transcription of FXN harboring short GAAs (depicted as a green line) in unaffected cells. (B) Transcriptional termination at the expanded GAA region (depicted as a red line) is initiated by formation of R-loops between the FXN mRNA and DNA template strand. R-loops can stimulate antisense transcription (either FAST1 or putative GAA-AS) at the GAA repeats. Recruitment of transcription factors to the GAAs can initiate synthesis of the antisense transcript at the repeat region. Bidirectional transcription of the expanded GAA•TTC sequences facilitates formation of a dsRNA between coding and non-coding strands, recruiting Ago/Dicer and histone methyltransferase (G9a), and leading to histone H3K9 methylation and HP1γ binding. Heterochromatin formation and appropriate sequence context (multiple PAS) result in recurrent, aberrant termination of RNA synthesis.

Mentions: Altogether, the formation of R-loops, increased levels of H3K9me2 and HP1γ binding, and the presence of the antisense FAST1 transcript all in proximity to the repeats in FRDA patient cells strongly suggest that a similar, RNAi-based transcription termination mechanism may be responsible for aberrant FXN silencing (Fig. 1). FAST1 expression is significantly higher in FRDA cells when compared to controls lacking expanded GAAs,15 thus mimicking R-loop stimulated antisense transcription at the termination regions.22 Moreover, the FAST1 transcript was also demonstrated to form a double-stranded RNA (dsRNA) with the FXN sense transcript, and the RNA duplex interacted with argonaute proteins, Ago 1 and Ago 2.24 However, the identified FXN-FAST1 dsRNA aligns to the transcription initiation region and not to the GAAs. Results of a recent genome-wide screen aimed to uncover a modulator of GAA repeat stability and fragility in yeast demonstrated that expanded GAAs serve as promoters and recruit transcription initiation factors,25 suggesting a potential mechanism to generate GAA•TTC dsRNA from the GAA repeat region. Therefore, either FAST1 is a longer antisense transcript originating at the GAA region, or a second putative antisense transcript is initiated at the expanded GAA repeats (Fig. 1B).Figure 1.


Friedreich's ataxia--a case of aberrant transcription termination?

Butler JS, Napierala M - Transcription (2015)

Proposed model of R-loop induced aberrant transcription termination of the FXN gene at the expanded GAA repeats. (A) Transcription of FXN harboring short GAAs (depicted as a green line) in unaffected cells. (B) Transcriptional termination at the expanded GAA region (depicted as a red line) is initiated by formation of R-loops between the FXN mRNA and DNA template strand. R-loops can stimulate antisense transcription (either FAST1 or putative GAA-AS) at the GAA repeats. Recruitment of transcription factors to the GAAs can initiate synthesis of the antisense transcript at the repeat region. Bidirectional transcription of the expanded GAA•TTC sequences facilitates formation of a dsRNA between coding and non-coding strands, recruiting Ago/Dicer and histone methyltransferase (G9a), and leading to histone H3K9 methylation and HP1γ binding. Heterochromatin formation and appropriate sequence context (multiple PAS) result in recurrent, aberrant termination of RNA synthesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581357&req=5

f0001: Proposed model of R-loop induced aberrant transcription termination of the FXN gene at the expanded GAA repeats. (A) Transcription of FXN harboring short GAAs (depicted as a green line) in unaffected cells. (B) Transcriptional termination at the expanded GAA region (depicted as a red line) is initiated by formation of R-loops between the FXN mRNA and DNA template strand. R-loops can stimulate antisense transcription (either FAST1 or putative GAA-AS) at the GAA repeats. Recruitment of transcription factors to the GAAs can initiate synthesis of the antisense transcript at the repeat region. Bidirectional transcription of the expanded GAA•TTC sequences facilitates formation of a dsRNA between coding and non-coding strands, recruiting Ago/Dicer and histone methyltransferase (G9a), and leading to histone H3K9 methylation and HP1γ binding. Heterochromatin formation and appropriate sequence context (multiple PAS) result in recurrent, aberrant termination of RNA synthesis.
Mentions: Altogether, the formation of R-loops, increased levels of H3K9me2 and HP1γ binding, and the presence of the antisense FAST1 transcript all in proximity to the repeats in FRDA patient cells strongly suggest that a similar, RNAi-based transcription termination mechanism may be responsible for aberrant FXN silencing (Fig. 1). FAST1 expression is significantly higher in FRDA cells when compared to controls lacking expanded GAAs,15 thus mimicking R-loop stimulated antisense transcription at the termination regions.22 Moreover, the FAST1 transcript was also demonstrated to form a double-stranded RNA (dsRNA) with the FXN sense transcript, and the RNA duplex interacted with argonaute proteins, Ago 1 and Ago 2.24 However, the identified FXN-FAST1 dsRNA aligns to the transcription initiation region and not to the GAAs. Results of a recent genome-wide screen aimed to uncover a modulator of GAA repeat stability and fragility in yeast demonstrated that expanded GAAs serve as promoters and recruit transcription initiation factors,25 suggesting a potential mechanism to generate GAA•TTC dsRNA from the GAA repeat region. Therefore, either FAST1 is a longer antisense transcript originating at the GAA region, or a second putative antisense transcript is initiated at the expanded GAA repeats (Fig. 1B).Figure 1.

Bottom Line: Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia.We propose a model of premature termination of FXN transcription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia.

View Article: PubMed Central - PubMed

Affiliation: a University of Alabama at Birmingham; Department of Biochemistry and Molecular Genetics ; UAB Stem Cell Institute ; Birmingham , AL USA.

ABSTRACT
Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia. We propose a model of premature termination of FXN transcription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia.

Show MeSH
Related in: MedlinePlus