Acta Neuropathologica

, Volume 134, Issue 5, pp 729–748 | Cite as

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

  • Junghee LeeEmail author
  • Yu Jin Hwang
  • Yunha Kim
  • Min Young Lee
  • Seung Jae Hyeon
  • Soojin Lee
  • Dong Hyun Kim
  • Sung Jae Jang
  • Hyoenjoo Im
  • Sun-Joon Min
  • Hyunah Choo
  • Ae Nim Pae
  • Dong Jin Kim
  • Kyung Sang Cho
  • Neil W. Kowall
  • Hoon RyuEmail author
Original Paper


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.


Huntington’s disease Heterochromatin Histone methyltransferase H3K9me3 Epigenome 



This study was supported by NIH Grant (R01 NS067283 and R01AG054156) (H.R.). This study was also supported by the National Research Foundation of Korea Grant (NRF-2015M3A9A8030034 and NRF-2016M3C7A1904233) from the Ministry of Science, ICT and Future Planning, the National Research Council of Science and Technology (NST) Grant (No. CRC-15-04-KIST) from the Korea government (MSIP), and Grants from Korea Institute of Science and Technology (2E26200 and 2E26663).

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Junghee Lee
    • 1
    • 2
    Email author
  • Yu Jin Hwang
    • 3
  • Yunha Kim
    • 3
  • Min Young Lee
    • 4
  • Seung Jae Hyeon
    • 3
  • Soojin Lee
    • 5
  • Dong Hyun Kim
    • 3
  • Sung Jae Jang
    • 3
  • Hyoenjoo Im
    • 3
  • Sun-Joon Min
    • 5
  • Hyunah Choo
    • 3
  • Ae Nim Pae
    • 7
  • Dong Jin Kim
    • 3
  • Kyung Sang Cho
    • 6
  • Neil W. Kowall
    • 1
    • 2
  • Hoon Ryu
    • 1
    • 2
    • 3
    Email author
  1. 1.VA Boston Healthcare SystemBostonUSA
  2. 2.Boston University Alzheimer’s Disease Center and Department of NeurologyBoston University School of MedicineBostonUSA
  3. 3.Center for Neuromedicine, Brain Science InstituteKorea Institute of Science and TechnologySeoulSouth Korea
  4. 4.Institute for Systems BiologySeattleUSA
  5. 5.Department of Chemical and Molecular Engineering/Applied ChemistryHanyang UniversityAnsanSouth Korea
  6. 6.Department of Biological SciencesKonkuk UniversitySeoulSouth Korea
  7. 7.Convergence Research Center for Diagnosis, Treatment, and Care System of DementiaKorea Institute of Science and TechnologySeoulSouth Korea

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