Pupak, Anika;
Rodriguez-Navarro, Irene;
Sathasivam, Kirupa;
Singh, Ankita;
Essmann, Amelie;
del Toro, Daniel;
Gines, Silvia;
... Brito, Veronica; + view all
(2024)
m6A modification of mutant huntingtin RNA promotes the biogenesis of pathogenic huntingtin transcripts.
EMBO Reports
, 25
(11)
pp. 5026-5052.
10.1038/s44319-024-00283-7.
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Abstract
In Huntington’s disease (HD), aberrant processing of huntingtin (HTT) mRNA produces HTT1a transcripts that encode the pathogenic HTT exon 1 protein. The mechanisms behind HTT1a production are not fully understood. Considering the role of m<sup>6</sup>A in RNA processing and splicing, we investigated its involvement in HTT1a generation. Here, we show that m<sup>6</sup>A methylation is increased before the cryptic poly(A) sites (IpA1 and IpA2) within the huntingtin RNA in the striatum of Hdh+/Q111 mice and human HD samples. We further assessed m<sup>6</sup>A’s role in mutant Htt mRNA processing by pharmacological inhibition and knockdown of METTL3, as well as targeted demethylation of Htt intron 1 using a dCas13-ALKBH5 system in HD mouse cells. Our data reveal that Htt1a transcript levels are regulated by both METTL3 and the methylation status of Htt intron 1. They also show that m<sup>6</sup>A methylation in intron 1 depends on expanded CAG repeats. Our findings highlight a potential role for m<sup>6</sup>A in aberrant splicing of Htt mRNA.
| Type: | Article |
|---|---|
| Title: | m6A modification of mutant huntingtin RNA promotes the biogenesis of pathogenic huntingtin transcripts |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s44319-024-00283-7 |
| Publisher version: | https://doi.org/10.1038/s44319-024-00283-7 |
| Language: | English |
| Additional information: | © 2024 The Author(s). 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, Huntington's Disease, Splicing, HTT1a, m(6)A, RNA Editing, MESSENGER-RNA, CAG REPEAT, MITOCHONDRIAL DYSFUNCTION, GENE-EXPRESSION, DISEASE, METHYLATION, REVEALS, N-6-METHYLADENOSINE, PHENOTYPE, MUTATION |
| UCL classification: | UCL 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 Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10217623 |
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