title: Activating frataxin expression by repeat-targeted nucleic acids.
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.
authors: Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center at Dallas, 6001 Forest Park Road, Dallas, Texas 75390-9041, USA.
authors: Liande
authors: L
authors: Li
authors: Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center at Dallas, 6001 Forest Park Road, Dallas, Texas 75390-9041, USA.
authors: Masayuki
authors: M
authors: Matsui
authors: Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center at Dallas, 6001 Forest Park Road, Dallas, Texas 75390-9041, USA.
authors: David R
authors: DR
authors: Corey
mesh_terms: D060565:Argonaute Proteins / Q000378:metabolism; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005621:Friedreich Ataxia / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D007438:Introns; D033862:Iron-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009696:Nucleic Acids / Q000494:pharmacology*; D012313:RNA / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019680:Trinucleotide Repeat Expansion; D000096923:Frataxin
chemical_list: D060565:Argonaute Proteins; D033862:Iron-Binding Proteins; D009696:Nucleic Acids; D012313:RNA; D012333:RNA, Messenger; D000096923:Frataxin; C466422:AGO2 protein, human