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

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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.

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Acknowledgements

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).

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  1. Junghee Lee, Yu Jin Hwang, Yunha Kim, Min Young Lee and Seung Jae Hyeon contributed equally.

Authors and Affiliations

  1. VA Boston Healthcare System, Boston, MA, 02130, USA

    Junghee Lee, Neil W. Kowall & Hoon Ryu

  2. Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA

    Junghee Lee, Neil W. Kowall & Hoon Ryu

  3. Center for Neuromedicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, South Korea

    Yu Jin Hwang, Yunha Kim, Seung Jae Hyeon, Dong Hyun Kim, Sung Jae Jang, Hyoenjoo Im, Hyunah Choo, Dong Jin Kim & Hoon Ryu

  4. Institute for Systems Biology, Seattle, WA, 98109, USA

    Min Young Lee

  5. Department of Chemical and Molecular Engineering/Applied Chemistry, Hanyang University, Ansan, 15588, South Korea

    Soojin Lee & Sun-Joon Min

  6. Department of Biological Sciences, Konkuk University, Seoul, 05029, South Korea

    Kyung Sang Cho

  7. Convergence Research Center for Diagnosis, Treatment, and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, South Korea

    Ae Nim Pae

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  1. Junghee Lee
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Lee, J., Hwang, Y.J., Kim, Y. et al. Remodeling of heterochromatin structure slows neuropathological progression and prolongs survival in an animal model of Huntington’s disease. Acta Neuropathol 134, 729–748 (2017). https://doi.org/10.1007/s00401-017-1732-8

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