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
Author
민선준
Keywords
Huntington's disease; Heterochromatin; Histone methyltransferase; H3K9me3; Epigenome; HISTONE DEACETYLASE INHIBITORS; H3 LYSINE-9 METHYLATION; TRANSGENIC MOUSE MODEL; CREB-BINDING PROTEIN; POLYGLUTAMINE TOXICITY; MAMMALIAN CHROMATIN; GENE-EXPRESSION; NERVOUS-SYSTEM; DNA-BINDING; TRANSCRIPTION
Issue Date
2017-11
Publisher
SPRINGER
Citation
ACTA NEUROPATHOLOGICA, v. 134, No. 5, Page. 729-748
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
https://link.springer.com/article/10.1007%2Fs00401-017-1732-8http://repository.hanyang.ac.kr/handle/20.500.11754/72653
ISSN
1432-0533; 0001-6322
DOI
10.1007/s00401-017-1732-8
Appears in Collections:
COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY[E](과학기술융합대학) > CHEMICAL AND MOLECULAR ENGINEERING(화학분자공학과) > Articles
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