{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:50:20Z","timestamp":1789023020859,"version":"build-2803163510"},"reference-count":30,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Huntington's Disease"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Gene silencing is widely recognized as a promising therapeutic approach for dominant monogenic disorders. Current silencing strategies, many of which are transient, utilize RNA interference. Gene silencing may also be achieved through directed epigenetic editing using a CRISPR\/dCas9 effector fused to DNA methyltransferase 3A (dCas9-DNMT3A). We used this system to direct DNA methylation to\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      , the causal gene underlying the autosomal dominant neurodegenerative disorder Huntington's disease, to assess the translational potential of this strategy for treating a genetic neurological disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To characterize the regulatory effect of targeted dCas9-DNMT3A-mediated DNA methylation at\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We exploited DNA methylation profiles of high and low\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      -expressing tissues and targeted hypomethylated regions of\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      associated with high levels of\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">De novo<\/jats:italic>\n                      DNA methylation of loci within defined upstream, promoter, intragenic and downstream regions of\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      resulted in robust, acute silencing of\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      . The best long-term silencing of\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      , which persisted up to 30 days, was observed when targeted DNA methylation was directed to the 5\u2019UTR and promoter regions of\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      gene silencing may be achieved via targeted\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      DNA methylation within hypomethylated regulatory regions at the\n                      <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                      locus. DNA methylation editing may be an attractive therapeutic approach for Huntington disease due to its potential for long-term silencing and reversibility.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/18796397251415368","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T18:25:58Z","timestamp":1769106358000},"page":"399-407","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Silencing of human\n                    <i>HTT<\/i>\n                    by targeted CRISPR\/dCas9-mediated epigenetic editing"],"prefix":"10.1177","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5175-4108","authenticated-orcid":false,"given":"Yi Lin","family":"Tay","sequence":"first","affiliation":[{"name":"Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9407-1245","authenticated-orcid":false,"given":"Sarah B","family":"Thomson","sequence":"additional","affiliation":[{"name":"University of British Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9987-5306","authenticated-orcid":false,"given":"Silvia","family":"Hnatova","sequence":"additional","affiliation":[{"name":"Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8809-7318","authenticated-orcid":false,"given":"Sherwin","family":"Ng","sequence":"additional","affiliation":[{"name":"Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si Rui","family":"Teo","sequence":"additional","affiliation":[{"name":"Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0876-0595","authenticated-orcid":false,"given":"Ryan","family":"McCallum","sequence":"additional","affiliation":[{"name":"University of British Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6229-4425","authenticated-orcid":false,"given":"Bernice","family":"Sim","sequence":"additional","affiliation":[{"name":"Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9191-4237","authenticated-orcid":false,"given":"Letizia","family":"Tarantini","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, EPIGET - Epidemiology, Epigenetics and Toxicology Laboratory, University of Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei Li","family":"Tai","sequence":"additional","affiliation":[{"name":"Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, Singapore, Singapore"},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Bollati","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, EPIGET - Epidemiology, Epigenetics and Toxicology Laboratory, University of Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3626-8466","authenticated-orcid":false,"given":"Marie","family":"Loh","sequence":"additional","affiliation":[{"name":"Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, Singapore, Singapore"},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5159-1419","authenticated-orcid":false,"given":"Michael R","family":"Hayden","sequence":"additional","affiliation":[{"name":"University of British Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4532-766X","authenticated-orcid":false,"given":"Blair R","family":"Leavitt","sequence":"additional","affiliation":[{"name":"University of British Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9030-0976","authenticated-orcid":false,"given":"Mahmoud A","family":"Pouladi","sequence":"additional","affiliation":[{"name":"Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, Singapore, Singapore"},{"name":"University of British Columbia"},{"name":"Department of Medical Genetics, Djavad Mowafaghian Centre for Brain Health, Edwin S. 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