Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington’s disease mouse model
Yu Jin Hwang, Seung Jae Hyeon, Young‐Hee Kim, Sungsu Lim, Min Young Lee, Jieun Kim, Ashwini M. Londhe, Lizaveta Gotina, Yunha Kim, Ae Nim Pae, Yong Seo Cho, Jihye Seong, Hyemyung Seo, Yun Kyung Kim, Hyunah Choo, Hoon Ryu, Sun‐Joon Min
Abstract
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.