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 a...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-09002-5 |
| _version_ | 1818353641263726592 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Layne N. Rodden |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T19:12:45Z |
| format | Article |
| id | doaj.art-a247ba32f3a94a45a9440487d667508d |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T19:12:45Z |
| publishDate | 2022-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a247ba32f3a94a45a9440487d667508d2022-12-21T23:34:22ZengNature PortfolioScientific Reports2045-23222022-03-0112111410.1038/s41598-022-09002-5DNA methylation in Friedreich ataxia silences expression of frataxin isoform ELayne N. Rodden0Kaitlyn M. Gilliam1Christina Lam2Teerapat Rojsajjakul3Clementina Mesaros4Chiara Dionisi5Mark Pook6Massimo Pandolfo7David R. Lynch8Ian A. Blair9Sanjay I. Bidichandani10Department of Pediatrics, University of Oklahoma Health Sciences Center, OU Children’s Physician BuildingDepartment of Pediatrics, University of Oklahoma Health Sciences Center, OU Children’s Physician BuildingDepartment of Pediatrics, University of Oklahoma Health Sciences Center, OU Children’s Physician BuildingDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of PennsylvaniaDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of PennsylvaniaUniversité Libre de Bruxelles (ULB)Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University LondonUniversité Libre de Bruxelles (ULB)Division of Neurology, The Children’s Hospital of PhiladelphiaDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of PennsylvaniaDepartment of Pediatrics, University of Oklahoma Health Sciences Center, OU Children’s Physician BuildingAbstract 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.https://doi.org/10.1038/s41598-022-09002-5 |
| spellingShingle | 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 DNA methylation in Friedreich ataxia silences expression of frataxin isoform E Scientific Reports |
| title | DNA methylation in Friedreich ataxia silences expression of frataxin isoform E |
| title_full | DNA methylation in Friedreich ataxia silences expression of frataxin isoform E |
| title_fullStr | DNA methylation in Friedreich ataxia silences expression of frataxin isoform E |
| title_full_unstemmed | DNA methylation in Friedreich ataxia silences expression of frataxin isoform E |
| title_short | DNA methylation in Friedreich ataxia silences expression of frataxin isoform E |
| title_sort | dna methylation in friedreich ataxia silences expression of frataxin isoform e |
| url | https://doi.org/10.1038/s41598-022-09002-5 |
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