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FAST-1 antisense RNA epigenetically alters FXN expression

Mikaeili, H; Sandi, M; Bayot, A; Al-Mahdawi, S; Pook, MA; (2018) FAST-1 antisense RNA epigenetically alters FXN expression. Scientific Reports , 8 , Article 17217 (2018). 10.1038/s41598-018-35639-2. Green open access

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Abstract

Friedreich ataxia (FRDA) is a multisystem genetic disorder caused by GAA repeat expansion mutations within the FXN gene, resulting in heterochromatin formation and defciency of frataxin protein. Elevated levels of the FXN antisense transcript (FAST-1) have previously been detected in FRDA. To investigate the efects of FAST-1 on the FXN gene expression, we frst stably overexpressed FAST1 in non-FRDA cell lines and then we knocked down FAST-1 in FRDA fbroblast cells. We observed decreased FXN expression in each FAST-1 overexpressing cell type compared to control cells. We also found that FAST-1 overexpression is associated with both CCCTC-Binding Factor (CTCF) depletion and heterochromatin formation at the 5′UTR of the FXN gene. We further showed that knocking down FAST-1 in FRDA fbroblast cells signifcantly increased FXN expression. Our results indicate that FAST-1 can act in trans in a similar manner to the cis-acting FAST-1 overexpression that has previously been identifed in FRDA fbroblasts. The efects of stably transfected FAST-1 expression on CTCF occupancy and heterochromatin formation at the FXN locus suggest a direct role for FAST-1 in the FRDA molecular disease mechanism. Our fndings also support the hypothesis that inhibition of FAST-1 may be a potential approach for FRDA therapy.

Type: Article
Title: FAST-1 antisense RNA epigenetically alters FXN expression
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-018-35639-2
Publisher version: https://doi.org/:10.1038/s41598-018-35639-2
Language: English
Additional information: Copyright © Te Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: http://discovery.ucl.ac.uk/id/eprint/10063412
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