DNA Methylation in Friedreich Ataxia Silences Expression of Frataxin Isoform E

Overview

Journal Sci Rep

Specialty Science

Date 2022 Mar 24

PMID 35322126

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

Affiliations

Soon will be listed here.

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.

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