2. Academic Validation
  3. Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington's disease mouse model

Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington's disease mouse model

  • J Enzyme Inhib Med Chem. 2021 Dec;36(1):856-868. doi: 10.1080/14756366.2021.1900160.
Yu Jin Hwang 1,  Seung Jae Hyeon 1,  Younghee Kim 1,  Sungsu Lim 2,  Min Young Lee 3,  Jieun Kim 1,  Ashwini M Londhe 2 4,  Lizaveta Gotina 2 4,  Yunha Kim 1,  Ae Nim Pae 2 4,  Yong Seo Cho 1 4,  Jihye Seong 2 4,  Hyemyung Seo 5,  Yun Kyung Kim 2 4,  Hyunah Choo 1 4,  Hoon Ryu 1 6,  Sun-Joon Min 7
Affiliations

Affiliations

  • 1 Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
  • 2 Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, Republic of Korea.
  • 3 Institute for Systems Biology, Seattle, WA, USA.
  • 4 Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea.
  • 5 Department of Molecular & Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea.
  • 6 Department of Neurology and Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA, USA.
  • 7 Department of Chemical & Molecular Engineering/Applied Chemistry, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea.
PMID: 33771089 DOI: 10.1080/14756366.2021.1900160
Abstract

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington's disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined in silico and in vitro cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model. In particular, not only APQ reduced H3K9me3 levels in the striatum but it also improved motor function and neuropathological symptoms such as neuronal size and activity in HD transgenic (YAC128) mice with minimal toxicity. Using H3K9me3-ChIP and genome-wide Sequencing, we also confirmed that APQ modulates H3K9me3-landscaped epigenomes in YAC128 mice. These data provide that APQ, a novel small molecule SETDB1 inhibitor, coordinates H3K9me-dependent heterochromatin remodelling and can be an epigenetic drug for treating HD, leading with hope in clinical trials of HD.

Keywords

Histone H3K9me3-specific transferase; Huntington’s disease; SETDB1; medium spiny neuron; motor function.

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