DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
23 03 2022
23 03 2022
Historique:
received:
07
11
2021
accepted:
14
03
2022
entrez:
24
3
2022
pubmed:
25
3
2022
medline:
6
5
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35322126
doi: 10.1038/s41598-022-09002-5
pii: 10.1038/s41598-022-09002-5
pmc: PMC8943190
doi:
Substances chimiques
Iron-Binding Proteins
0
Protein Isoforms
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5031Subventions
Organisme : NINDS NIH HHS
ID : U01 NS114143
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES013508
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS072418
Pays : United States
Informations de copyright
© 2022. The Author(s).
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