DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.

Abstract

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.

• Authors: Layne N Rodden, Kaitlyn M Gilliam, Christina Lam, Teerapat Rojsajjakul, Clementina Mesaros, Chiara Dionisi, Mark Pook, Massimo Pandolfo, David R Lynch, Ian A Blair, Sanjay I Bidichandani
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 5031 (03 23 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35322126 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Iron-Binding Proteins
• Protein Isoforms
• frataxin
• DNA

Topics

• Animals
• DNA (metabolism)
• DNA Methylation
• Friedreich Ataxia (genetics)
• Humans
• Iron-Binding Proteins (genetics, metabolism)
• Mice
• Protein Isoforms (metabolism)
• Trinucleotide Repeat Expansion