한빛사 논문
Junghee Lee1,2,*, Yu Jin Hwang3, Yunha Kim3, Min Young Lee4, Seung Jae Hyeon3, Soojin Lee5, Dong Hyun Kim3, Sung Jae Jang3, Hyoenjoo Im3, Sun-Joon Min5, Hyunah Choo3, Ae Nim Pae7, Dong Jin Kim3, Kyung Sang Cho6, Neil W. Kowall1,2, Hoon Ryu1,2,3,*
1 VA Boston Healthcare System, Boston, USA
2 Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University School of Medicine, Boston, USA
3 Center for Neuromedicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
4 Institute for Systems Biology, Seattle, USA
5 Department of Chemical and Molecular Engineering/Applied Chemistry, Hanyang University, Ansan, South Korea
6 Department of Biological Sciences, Konkuk University, Seoul, South Korea
7 Convergence Research Center for Diagnosis, Treatment, and Care System of Dementia, Korea Institute of Science and Technology, Seoul, South Korea
Junghee Lee, Yu Jin Hwang, Yunha Kim, Min Young Lee and Seung Jae Hyeon contributed equally.
*To whom correspondence may be addressed.
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.
Keywords : Huntington’s disease, Heterochromatin, Histone methyltransferase, H3K9me3, Epigenome
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