Journal Article

DNA methylation in Friedreich ataxia silences expression of frataxin isoform E

Pandolfo, Massimo, Bidichandani, Sanjay I., Pook, Mark, Dionisi, Chiara, Rojsajjakul, Teerapat, Mesaros, Clementina, Lynch, David R., Gilliam, Kaitlyn M., Blair, Ian A., Rodden, Layne N., Lam, Christina

2022

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/208 / 692/617 / Animals / Ataxia / Cell lines / CRISPR / Deoxyribonucleic acid / DNA / DNA - metabolism / DNA Methylation / E protein / Epigenetics / Erythrocytes / Frataxin / Friedreich Ataxia - genetics / Friedreich's ataxia / Humanities and Social Sciences / Humans / Iron-Binding Proteins - genetics / Iron-Binding Proteins - metabolism / Mice / Mitochondria / multidisciplinary / Proprioception / Protein deficiency / Protein Isoforms - metabolism / Science / Science (multidisciplinary) / Transcription / Trinucleotide Repeat Expansion