Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cells

Abnormally expanded DNA repeats are associated with several neurodegenerative diseases. In Friedreich's ataxia (FRDA), expanded GAA repeats in intron 1 of the frataxin gene (FXN) reduce FXN mRNA levels in averaged cell samples through a poorly understood mechanism. By visualizing FXN expression...

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Bibliographic Details
Published in:Human molecular genetics 2015-06, Vol.24 (12), p.3457-3471
Main Authors: Silva, Ana M, Brown, Jill M, Buckle, Veronica J, Wade-Martins, Richard, Lufino, Michele M P
Format: Article
Language:English
Subjects:
Alleles
Cell Line
Frataxin
Gene Expression
Gene Order
Gene Silencing
Genetic Loci
Humans
Iron-Binding Proteins - genetics
Iron-Binding Proteins - metabolism
Nuclear Lamina - metabolism
Protein Transport
RNA, Messenger - genetics
Single-Cell Analysis
Transcription Initiation Site
Transcription Initiation, Genetic
Transcription, Genetic
Trinucleotide Repeat Expansion
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Summary:Abnormally expanded DNA repeats are associated with several neurodegenerative diseases. In Friedreich's ataxia (FRDA), expanded GAA repeats in intron 1 of the frataxin gene (FXN) reduce FXN mRNA levels in averaged cell samples through a poorly understood mechanism. By visualizing FXN expression and nuclear localization in single cells, we show that GAA-expanded repeats decrease the number of FXN mRNA molecules, slow transcription, and increase FXN localization at the nuclear lamina (NL). Restoring histone acetylation reverses NL positioning. Expanded GAA-FXN loci in FRDA patient cells show increased NL localization with increased silencing of alleles and reduced transcription from alleles positioned peripherally. We also demonstrate inefficiencies in transcription initiation and elongation from the expanded GAA-FXN locus at single-cell resolution. We suggest that repressive epigenetic modifications at the expanded GAA-FXN locus may lead to NL relocation, where further repression may occur.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddv096