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FARAFARA Cure FA

FAST-1 antisense RNA epigenetically alters FXN expression

Friedreich ataxia (FRDA) is a multisystem genetic disorder caused by GAA repeat expansion mutations within the FXN gene, resulting in heterochromatin formation and deficiency of frataxin protein. Elevated levels of the FXN antisense transcript (FAST-1) have previously been detected in FRDA. To investigate the effects of FAST-1 on the FXN gene expression, this group looked at effects of FAST-1 in non-FRDA cell lines and in FRDA fibroblast cells. They observed decreased FXN expression in each FAST-1 overexpressing cell type compared to control cells and found that FAST-1 overexpression is associated with both CCCTC-Binding Factor (CTCF) depletion and heterochromatin formation at the 5'UTR of the FXN gene. Knocking down FAST-1 in FRDA cells significantly increased FXN expression. The effects of FAST-1 expression on the FXN locus suggest a direct role for FAST-1 in the FRDA molecular disease mechanism and support the hypothesis that inhibition of FAST-1 may be a potential approach for FRDA therapy.

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Jane Larkindale

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