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Title: | DNA methylation in Friedreich ataxia silences expression of frataxin isoform E |
Authors: | Rodden, LN Gilliam, KM Lam, C Rojsajjakul, T Mesaros, C Dionisi, C Pook, M Pandolfo, M Lynch, DR Blair, IA Bidichandani, SI |
Keywords: | genetics;neurology |
Issue Date: | 23-Mar-2022 |
Publisher: | Springer Nature |
Citation: | Rodden, L.N., Gilliam, K.M., Lam, C. et al. (2022) 'DNA methylation in Friedreich ataxia silences expression of frataxin isoform E. Scientific Reports, 12, 5031 pp. 1-14. doi: 10.1038/s41598-022-09002-5. |
Abstract: | Copyright © 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. |
Description: | Supplementary Information: https://static-content.springer.com/esm/art%3A10.1038%2Fs41598-022-09002-5/MediaObjects/41598_2022_9002_MOESM1_ESM.pdf |
URI: | https://bura.brunel.ac.uk/handle/2438/24517 |
DOI: | https://doi.org/10.1038/s41598-022-09002-5 |
Other Identifiers: | 5031 |
Appears in Collections: | Dept of Life Sciences Research Papers |
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