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

Autor:	Sungsu Lim, Sun-Joon Min, Yun Kyung Kim, Younghee Kim, Hyunah Choo, Lizaveta Gotina, Yu Jin Hwang, Hoon Ryu, Y. S. Kim, Ashwini M. Londhe, Jihye Seong, Min Young Lee, Ae Nim Pae, Jieun Kim, Seung Jae Hyeon, Yong Seo Cho, Hyemyung Seo
Rok vydání:	2021
Předmět:	Cell Survival Heterochromatin Mice Transgenic RM1-950 Biosensing Techniques Neuropathology Biology Medium spiny neuron medium spiny neuron 01 natural sciences Motor function Mice Huntington's disease Drug Discovery Fluorescence Resonance Energy Transfer SETDB1 medicine Animals Epigenetics Enzyme Inhibitors Cells Cultured Neurons Pharmacology Behavior Animal Molecular Structure 010405 organic chemistry motor function Histone-Lysine N-Methyltransferase General Medicine Histone H3K9me3-specific transferase medicine.disease Small molecule 0104 chemical sciences Disease Models Animal 010404 medicinal & biomolecular chemistry Huntington Disease Therapeutics. Pharmacology Neuroscience Research Article Research Paper Huntington’s disease
Zdroj:	Journal of Enzyme Inhibition and Medicinal Chemistry article-version (VoR) Version of Record Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 856-868 (2021)
ISSN:	1475-6374 1475-6366
DOI:	10.1080/14756366.2021.1900160
Popis:	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. Graphical Abstract
Databáze:	OpenAIRE
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