DNA methylation in Friedreich ataxia silences expression of frataxin isoform E

Supplementary Information: https://static-content.springer.com/esm/art%3A10.1038%2Fs41598-022-09002-5/MediaObjects/41598_2022_9002_MOESM1_ESM.pdfCopyright © The Author(s) 2022. Epigenetic silencing in Friedreich ataxia (FRDA), induced by an expanded GAA triplet-repeat in intron 1 of the FXN gene, results in deficiency of the mitochondrial protein, frataxin. A lesser known extramitochondrial isoform of frataxin detected in erythrocytes, frataxin-E, is encoded via an alternate transcript (FXN-E) originating in intron 1 that lacks a mitochondrial targeting sequence. We show that FXN-E is deficient in FRDA, including in patient-derived cell lines, iPS-derived proprioceptive neurons, and tissues from a humanized mouse model. In a series of FRDA patients, deficiency of frataxin-E protein correlated with the length of the expanded GAA triplet-repeat, and with repeat-induced DNA hypermethylation that occurs in close proximity to the intronic origin of FXN-E. CRISPR-induced epimodification to mimic DNA hypermethylation seen in FRDA reproduced FXN-E transcriptional deficiency. Deficiency of frataxin E is a consequence of FRDA-specific epigenetic silencing, and therapeutic strategies may need to address this deficiency.National Institutes of Health [R01 NS072418; P30 ES013508; U01 NS114143; Muscular Dystrophy Association [MDA604011; Friedreich Ataxia Research Alliance; CureFA Foundation