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Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cells

2015Journal article Restricted access
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dc.contributor.authorSilva, Ana M.
dc.contributor.authorBrown, Jill M.
dc.contributor.authorBuckle, Veronica J.
dc.contributor.authorWade-Martins, Richard
dc.contributor.authorLufino, Michele M. P.
dc.date.accessioned2022-06-14T16:15:21Z
dc.date.available2022-06-14T16:15:21Z
dc.date.issued2015
dc.description© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.compt_PT
dc.description.abstractAbnormally expanded DNA repeats are associated with several neurodegenerative diseases. In Friedreich's ataxia (FRDA), expanded GAA repeats in intron 1 of the frataxin gene (FXN) reduce FXN mRNA levels in averaged cell samples through a poorly understood mechanism. By visualizing FXN expression and nuclear localization in single cells, we show that GAA-expanded repeats decrease the number of FXN mRNA molecules, slow transcription, and increase FXN localization at the nuclear lamina (NL). Restoring histone acetylation reverses NL positioning. Expanded GAA-FXN loci in FRDA patient cells show increased NL localization with increased silencing of alleles and reduced transcription from alleles positioned peripherally. We also demonstrate inefficiencies in transcription initiation and elongation from the expanded GAA-FXN locus at single-cell resolution. We suggest that repressive epigenetic modifications at the expanded GAA-FXN locus may lead to NL relocation, where further repression may occur.pt_PT
dc.description.sponsorshipThis work was supported by Ataxia UK (fellowship no. 7125 to M.M.L.), the Friedreich's Ataxia Research Alliance (FARA) (to M.M.L. and R.W.-M.), BabelFAmily (to M.M.L.), Associazione Italiana per la lotta alle Sindromi Atassiche (AISA) (to M.M.L.), the European Union 7th Framework Program EFACTS (grant agreement no. 242193) (to R.W.-M.). M.M.L. is an Ataxia UK research fellow co-funded by FARA and AISA. A.M.S. was supported by Fundação para a Ciência e a Tecnologia PhD studentship (SFRH/BD/61048/2009). Advanced microscopy at Micron Oxford was supported by a Wellcome Trust Strategic Award (091911).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationHum Mol Genet. 2015 Jun 15;24(12):3457-3471pt_PT
dc.identifier.doi10.1093/hmg/ddv096pt_PT
dc.identifier.eissn1460-2083
dc.identifier.issn0964-6906
dc.identifier.urihttp://hdl.handle.net/10451/53384
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Presspt_PT
dc.relationEuropean Friedreich's Ataxia Consortium for Translational Studies
dc.relationUSE OF GENOMIC DNA-REPORTER TOOLS TO DISSECT PATHOLOGICAL MECHANISMS CAUSED BY GAA EXPANSIONS IN FRIEDREICH’S ATAXIA
dc.relationAdvanced Microscopy for Chromosome and RNA Dynamics.
dc.relation.publisherversionhttps://academic.oup.com/hmgpt_PT
dc.titleExpanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleEuropean Friedreich's Ataxia Consortium for Translational Studies
oaire.awardTitleUSE OF GENOMIC DNA-REPORTER TOOLS TO DISSECT PATHOLOGICAL MECHANISMS CAUSED BY GAA EXPANSIONS IN FRIEDREICH’S ATAXIA
oaire.awardTitleAdvanced Microscopy for Chromosome and RNA Dynamics.
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/242193/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/PIDDAC/SFRH%2FBD%2F61048%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/WT/Cellular and Molecular Neuroscience/091911
oaire.citation.endPage3471pt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPage3457pt_PT
oaire.citation.titleHuman Molecular Geneticspt_PT
oaire.citation.volume24pt_PT
oaire.fundingStreamFP7
oaire.fundingStreamPIDDAC
oaire.fundingStreamCellular and Molecular Neuroscience
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/100010269
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameWellcome Trust
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication373d1313-3cbc-49c6-9927-96ba1df9d8fe
relation.isProjectOfPublication028e54bd-260b-4dcc-b4a7-5107abcc67c3
relation.isProjectOfPublication7e634147-6dd9-41fb-99a4-6dbc11f738ac
relation.isProjectOfPublication.latestForDiscovery028e54bd-260b-4dcc-b4a7-5107abcc67c3

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