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The mechanisms behind\n                    <jats:italic>HTT1a<\/jats:italic>\n                    production are not fully understood. Considering the role of m\n                    <jats:sup>6<\/jats:sup>\n                    A in RNA processing and splicing, we investigated its involvement in\n                    <jats:italic>HTT1a<\/jats:italic>\n                    generation. Here, we show that m\n                    <jats:sup>6<\/jats:sup>\n                    A methylation is increased before the cryptic poly(A) sites (IpA1 and IpA2) within the huntingtin RNA in the striatum of\n                    <jats:italic>Hdh+\/Q111<\/jats:italic>\n                    mice and human HD samples. We further assessed m\n                    <jats:sup>6<\/jats:sup>\n                    A\u2019s role in mutant\n                    <jats:italic>Htt<\/jats:italic>\n                    mRNA processing by pharmacological inhibition and knockdown of METTL3, as well as targeted demethylation of\n                    <jats:italic>Htt<\/jats:italic>\n                    intron 1 using a dCas13-ALKBH5 system in HD mouse cells. Our data reveal that\n                    <jats:italic>Htt1a<\/jats:italic>\n                    transcript levels are regulated by both METTL3 and the methylation status of\n                    <jats:italic>Htt<\/jats:italic>\n                    intron 1. They also show that m\n                    <jats:sup>6<\/jats:sup>\n                    A methylation in intron 1 depends on expanded CAG repeats. Our findings highlight a potential role for m\n                    <jats:sup>6<\/jats:sup>\n                    A in aberrant splicing of\n                    <jats:italic>Htt<\/jats:italic>\n                    mRNA.\n                  <\/jats:p>","DOI":"10.1038\/s44319-024-00283-7","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T05:02:04Z","timestamp":1728622924000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["m6A modification of mutant huntingtin RNA promotes the biogenesis of pathogenic huntingtin transcripts"],"prefix":"10.1038","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2653-9189","authenticated-orcid":false,"given":"Anika","family":"Pupak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Rodr\u00edguez-Navarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirupa","family":"Sathasivam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8339-3337","authenticated-orcid":false,"given":"Ankita","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelie","family":"Essmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"del Toro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9479-8185","authenticated-orcid":false,"given":"Silvia","family":"Gin\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6744-2805","authenticated-orcid":false,"given":"Ricardo","family":"Mouro Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian P","family":"Bates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0643-0592","authenticated-orcid":false,"given":"Ulf Andersson","family":"Vang \u00d8rom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eul\u00e0lia","family":"Mart\u00ed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4137-0708","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"Brito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"key":"283_CR1","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1080\/15476286.2016.1201628","volume":"13","author":"S Adhikari","year":"2016","unstructured":"Adhikari S, Xiao W, Zhao Y-L, Yang Y-G (2016) m 6 A: signaling for mRNA splicing. 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