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Using an epigenetic pathway-targeted drug screen, we report that inhibitors of DNA methyltransferases (DNMTs), decitabine and FdCyd, block mutant huntingtin (Htt)-induced toxicity in primary cortical and striatal neurons. In addition, knockdown of DNMT3A or DNMT1 protected neurons against mutant Htt-induced toxicity, together demonstrating a requirement for DNMTs in mutant Htt-triggered neuronal death and suggesting a neurodegenerative mechanism based on DNA methylation-mediated transcriptional repression. Inhibition of DNMTs in HD model primary cortical or striatal neurons restored the expression of several key genes, including\n                    <jats:italic>Bdnf<\/jats:italic>\n                    , an important neurotrophic factor implicated in HD. Accordingly, the\n                    <jats:italic>Bdnf<\/jats:italic>\n                    promoter exhibited aberrant cytosine methylation in mutant Htt-expressing cortical neurons.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , pharmacological inhibition of DNMTs in HD mouse brains restored the mRNA levels of key striatal genes known to be downregulated in HD. Thus, disturbances in DNA methylation play a critical role in mutant Htt-induced neuronal dysfunction and death, raising the possibility that epigenetic strategies targeting abnormal DNA methylation may have therapeutic utility in HD.\n                  <\/jats:p>","DOI":"10.1038\/srep31022","type":"journal-article","created":{"date-parts":[[2016,8,12]],"date-time":"2016-08-12T05:45:56Z","timestamp":1470980756000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity"],"prefix":"10.1038","volume":"6","author":[{"given":"Yanchun","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuji","family":"Daito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yo","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Hee","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyun","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santhi","family":"Pondugula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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