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%2Fs00401-017-1732-8https://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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