Remodeling of heterochromatin structure slows neuropathological progression and prolongs survival in an animal model of Huntington’s disease

Title
Remodeling of heterochromatin structure slows neuropathological progression and prolongs survival in an animal model of Huntington’s disease
Authors
김동진배애님추현아류훈김연하황유진현승재김동현임현주Junghee LeeMin Young LeeSoojin LeeKyung Sang ChoNeil W. KowallSung Jae JangSun?Joon Min
Keywords
Epigenom; H3K9me3; Heterochromatin; Histone methyltransferase; Huntington’s disease
Issue Date
2017-11
Publisher
Acta neuropathologica
Citation
VOL 135, NO 5-748
Abstract
Huntington'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.
URI
http://pubs.kist.re.kr/handle/201004/67226
ISSN
0001-6322
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KIST Publication > Article
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