Activating frataxin expression by repeat-targeted nucleic acids

Liande Li, Masayuki Matsui, David R. Corey

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Friedreich's ataxia is an incurable genetic disorder caused by a mutant expansion of the trinucleotide GAA within an intronic FXN RNA. This expansion leads to reduced expression of frataxin (FXN) protein and evidence suggests that transcriptional repression is caused by an R-loop that forms between the expanded repeat RNA and complementary genomic DNA. Synthetic agents that increase levels of FXN protein might alleviate the disease. We demonstrate that introducing anti-GAA duplex RNAs or single-stranded locked nucleic acids into patient-derived cells increases FXN protein expression to levels similar to analogous wild-type cells. Our data are significant because synthetic nucleic acids that target GAA repeats can be lead compounds for restoring curative FXN levels. More broadly, our results demonstrate that interfering with R-loop formation can trigger gene activation and reveal a new strategy for upregulating gene expression.

Original languageEnglish (US)
Article number10606
JournalNature Communications
Volume7
DOIs
StatePublished - Feb 4 2016

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nucleic acids
Nucleic Acids
proteins
complementary DNA
ataxia
lead compounds
RNA
expansion
gene expression
cells
genes
Friedreich Ataxia
Lead compounds
actuators
Complementary RNA
Inborn Genetic Diseases
Proteins
activation
disorders
Gene expression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Activating frataxin expression by repeat-targeted nucleic acids. / Li, Liande; Matsui, Masayuki; Corey, David R.

In: Nature Communications, Vol. 7, 10606, 04.02.2016.

Research output: Contribution to journalArticle

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