{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:30:01Z","timestamp":1791052201589,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2017,5,19]],"date-time":"2017-05-19T00:00:00Z","timestamp":1495152000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA025697"],"award-info":[{"award-number":["DA025697"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA030177"],"award-info":[{"award-number":["DA030177"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Huntington's disease (<jats:styled-content style=\"fixed-case\">HD<\/jats:styled-content>) is caused by a genetically mutated huntingtin (<jats:styled-content style=\"fixed-case\">mH<\/jats:styled-content>tt) protein with expanded polyQ stretch, which impairs cytosolic sequestration of the repressor element\u20101 silencing transcription factor (<jats:styled-content style=\"fixed-case\">REST<\/jats:styled-content>), resulting in excessive nuclear <jats:styled-content style=\"fixed-case\">REST<\/jats:styled-content> and subsequent repression of neuronal genes. We recently demonstrated that <jats:italic><jats:styled-content style=\"fixed-case\">REST<\/jats:styled-content><\/jats:italic> undergoes extensive, context\u2010dependent alternative splicing, of which exon\u20103 skipping (\u2206E<jats:sub>3<\/jats:sub>)\u2014a common event in human and nonhuman primates\u2014causes loss of a motif critical for <jats:styled-content style=\"fixed-case\">REST<\/jats:styled-content> nuclear targeting. This study aimed to determine whether \u2206E<jats:sub>3<\/jats:sub> can be targeted to reduce nuclear <jats:styled-content style=\"fixed-case\">REST<\/jats:styled-content> and rescue neuronal gene expression in mouse striatal\u2010derived, <jats:styled-content style=\"fixed-case\">mH<\/jats:styled-content>tt\u2010expressing <jats:styled-content style=\"fixed-case\">STH<\/jats:styled-content>dh<jats:sup>Q111\/Q111<\/jats:sup> cells\u2014a well\u2010established cellular model of <jats:styled-content style=\"fixed-case\">HD<\/jats:styled-content>. We designed two morpholino antisense oligos (<jats:styled-content style=\"fixed-case\">ASO<\/jats:styled-content>s) targeting the splice sites of <jats:italic>Rest<\/jats:italic> E<jats:sub>3<\/jats:sub> and examined their effects on \u2206E<jats:sub>3<\/jats:sub>, nuclear Rest accumulation and Rest\u2010controlled gene expression in <jats:styled-content style=\"fixed-case\">STH<\/jats:styled-content>dh<jats:sup>Q111\/Q111<\/jats:sup> cells. We found that (1) the <jats:styled-content style=\"fixed-case\">ASO<\/jats:styled-content>s treatment significantly induced \u2206E<jats:sub>3<\/jats:sub>, reduced nuclear Rest, and rescued transcription and\/or mis\u2010splicing of specific neuronal genes (<jats:italic>e.g. Syn1<\/jats:italic> and <jats:italic>Stmn2<\/jats:italic>) in <jats:styled-content style=\"fixed-case\">STH<\/jats:styled-content>dh<jats:sup>Q111\/Q111<\/jats:sup> cells; and (2) the <jats:styled-content style=\"fixed-case\">ASO<\/jats:styled-content>s\u2010induced transcriptional regulation was dependent on \u2206E<jats:sub>3<\/jats:sub> induction and mimicked by si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010mediated knock\u2010down of <jats:italic>Rest<\/jats:italic> expression. Our findings demonstrate modulation of nuclear <jats:styled-content style=\"fixed-case\">REST<\/jats:styled-content> by \u2206E<jats:sub>3<\/jats:sub> and its potential as a new therapeutic target for <jats:styled-content style=\"fixed-case\">HD<\/jats:styled-content> and provide new insights into environmental regulation of genome function and pathogenesis of <jats:styled-content style=\"fixed-case\">HD<\/jats:styled-content>. As \u2206E<jats:sub>3<\/jats:sub> is modulated by cellular signalling and linked to various types of cancer, we anticipate that \u2206E<jats:sub>3<\/jats:sub> contributes to environmentally tuned <jats:styled-content style=\"fixed-case\">REST<\/jats:styled-content> function and may have a broad range of clinical implications.<\/jats:p>","DOI":"10.1111\/jcmm.13209","type":"journal-article","created":{"date-parts":[[2017,5,19]],"date-time":"2017-05-19T10:45:44Z","timestamp":1495190744000},"page":"2974-2984","source":"Crossref","is-referenced-by-count":26,"title":["Modulation of nuclear <scp>REST<\/scp> by alternative splicing: a potential therapeutic target for Huntington's disease"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9236-1385","authenticated-orcid":false,"given":"Guo\u2010Lin","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences and Center for Drug Discovery School of Pharmacy Northeastern University Boston MA USA"},{"name":"Guangxi Collaborative Innovation Center for Biomedicine Guangxi Medical University Nanning Guangxi China"},{"name":"Research Center for Regenerative Medicine of Guangxi Guangxi Medical University Nanning Guangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Institute for Human Performance SUNY Upstate Medical University Syracuse NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dharmendra","family":"Goswami","sequence":"additional","affiliation":[{"name":"Center for the Study of Traumatic Encephalopathy Boston University School of Medicine Boston MA USA"},{"name":"Department of Neurology Boston University School of Medicine Boston MA USA"},{"name":"VA Boston HealthCare System Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyu","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Center for Drug Discovery School of Pharmacy Northeastern University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Center for Drug Discovery School of Pharmacy Northeastern University Boston MA USA"},{"name":"Department of Chemical Engineering School of Engineering Northeastern University Boston MA 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