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dc.contributor.author김동진-
dc.contributor.author배애님-
dc.contributor.author추현아-
dc.contributor.author류훈-
dc.contributor.author김연하-
dc.contributor.author황유진-
dc.contributor.author현승재-
dc.contributor.author김동현-
dc.contributor.author임현주-
dc.contributor.authorJunghee Lee-
dc.contributor.authorMin Young Lee-
dc.contributor.authorSoojin Lee-
dc.contributor.authorKyung Sang Cho-
dc.contributor.authorNeil W. Kowall-
dc.contributor.authorSung Jae Jang-
dc.contributor.authorSun?Joon Min-
dc.date.accessioned2021-06-09T04:19:38Z-
dc.date.available2021-06-09T04:19:38Z-
dc.date.issued2017-11-
dc.identifier.citationVOL 135, NO 5-748-
dc.identifier.issn0001-6322-
dc.identifier.other50339-
dc.identifier.urihttp://pubs.kist.re.kr/handle/201004/67226-
dc.description.abstractHuntington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. Altered histone modifications and epigenetic mechanisms are closely associated with HD suggesting that transcriptional repression may play a pathogenic role. Epigenetic compounds have significant therapeutic effects in cellular and animal models of HD, but they have not been successful in clinical trials. Herein, we report that dSETDB1/ESET, a histone methyltransferase (HMT), is a mediator of mutant HTT-induced degeneration in a fly HD model. We found that nogalamycin, an anthracycline antibiotic and a chromatin remodeling drug, reduces trimethylated histone H3K9 (H3K9me3) levels and pericentromeric heterochromatin condensation by reducing the expression of Setdb1/Eset. H3K9me3-specific ChIP-on-ChIP analysis identified that the H3K9me3-enriched epigenome signatures of multiple neuronal pathways including Egr1, Fos, Ezh1, and Arc are deregulated in HD transgenic (R6/2) mice. Nogalamycin modulated the expression of the H3K9me3-landscaped epigenome in medium spiny neurons and reduced mutant HTT nuclear inclusion formation. Moreover, nogalamycin slowed neuropathological progression, preserved motor function, and extended the life span of R6/2 mice. Together, our results indicate that modulation of SETDB1/ESET and H3K9me3-dependent heterochromatin plasticity is responsible for the neuroprotective effects of nogalamycin in HD and that small compounds targeting dysfunctional histone modification and epigenetic modification by SETDB1/ESET may be a rational therapeutic strategy in HD.-
dc.publisherActa neuropathologica-
dc.subjectEpigenom-
dc.subjectH3K9me3-
dc.subjectHeterochromatin-
dc.subjectHistone methyltransferase-
dc.subjectHuntington’s disease-
dc.titleRemodeling of heterochromatin structure slows neuropathological progression and prolongs survival in an animal model of Huntington’s disease-
dc.typeArticle-
dc.relation.page729748-
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