FAST-1 antisense RNA epigenetically alters FXN expression

Abstract

Copyright © The Author(s) 2018. 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, we first stably overexpressed FAST-1 in non-FRDA cell lines and then we knocked down FAST-1 in FRDA fibroblast cells. We observed decreased FXN expression in 3 each FAST-1 overexpressing cell type compared to control cells. We also 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. We further showed that knocking down FAST-1 in FRDA fibroblast cells significantly increased FXN expression. Our results indicate that FAST-1 can act in Trans in a similar manner to the cis-acting FAST-1 overexpression that has previously been identified in FRDA fibroblasts. The effects of stably transfected FAST-1 expression on CTCF occupancy and heterochromatin formation at the FXN locus suggest a direct role for FAST- 1 in the FRDA molecular disease mechanism. Our findings also support the hypothesis that inhibition of FAST-1 may be a potential approach 40 for FRDA therapy.1 in the FRDA molecular disease mechanism. Our findings also support the hypothesis that inhibition of FAST-1 may be a potential approach for FRDA therapy.European Union Seventh Framework Programm