Long intronic GAA repeats causing Friedreich ataxia impede transcription elongation

Friedreich ataxia is a degenerative disease caused by deficiency of the protein frataxin (FXN). An intronic expansion of GAA triplets in the FXN-encoding gene, FXN, causes gene silencing and thus reduced FXN protein levels. Although it is widely assumed that GAA repeats block transcription via the assembly of an inaccessible chromatin structure marked by methylated H3K9, direct proof for this is lacking. In this study, we analysed different histone modification patterns along the human FXN gene in FRDA patient-derived lymphoblastoid cell lines. We show that FXN mRNA synthesis, but not turnover rates are affected by an expanded GAA repeat tract. Importantly, rather than preventing transcription initiation, long GAA repeat tracts affect transcription at the elongation step and this can occur independently of H3K9 methylation. Our data demonstrate that finding novel strategies to overcome the transcription elongation problem may develop into promising new treatments for FRDA.