Remodeling of heterochromatin structure slows neuropathological progression and prolongs survival in an animal model of Huntington's disease.
Animals; Chromatin Assembly and Disassembly; Chromatin Immunoprecipitation; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Heterochromatin; Histone-Lysine N-Methyltransferase; Huntington Disease; Mice; Survival Rate
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.
Neurosciences (Brain & Spine)
Institute for Systems Biology
Lee, Junghee; Hwang, Yu Jin; Kim, Yunha; Lee, Min Young; Hyeon, Seung Jae; Lee, Soojin; Kim, Dong Hyun; Jang, Sung Jae; Im, Hyoenjoo; Min, Sun-Joon; Choo, Hyunah; Pae, Ae Nim; Kim, Dong Jin; Cho, Kyung Sang; Kowall, Neil W; and Ryu, Hoon, "Remodeling of heterochromatin structure slows neuropathological progression and prolongs survival in an animal model of Huntington's disease." (2017). Articles, Abstracts, and Reports. 1340.