The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer’s disease and Huntington’s disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA-binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer’s disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders.

中文翻译：

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Dlg4 / PSD95基因的表观遗传编辑可改善老年和阿尔茨海默氏病小鼠的认知

该Dlg4对突触后密度蛋白95（PSD95）基因编码，一个主要的突触蛋白簇谷氨酸受体并且是塑性的关键。在衰老和神经退行性疾病（包括阿尔茨海默氏病和亨廷顿氏病）中，PSD95的水平降低。（dys）调节Dlg4 / PSD95，或其他可塑性基因的转录的表观遗传机制很大程度上未知，这限制了靶向表观基因组疗法的发展。我们分析了海马组织中的Dlg4 / PSD95表观遗传景观，并设计了Dlg4 / PSD95基因靶向策略：Dlg4/ PSD95锌指DNA结合结构域经工程改造并融合到效应子结构域上，以阻抑（G9a，Suvdel76，SKD）或激活（VP64）转录，生成人工转录因子或表观遗传编辑器（甲基化H3K9）。这些Epi编辑器改变了关键的组蛋白标记，随后改变了Dlg4 / PSD95的表达，重要的是，它影响了多个海马神经元的可塑性过程。有趣的是，人工转录因子PSD95-VP64的转导挽救了老年和阿尔茨海默氏病小鼠的记忆缺陷。结论是，这项工作验证了PSD95作为记忆的关键因素，并将表观遗传编辑确立为治疗人类神经系统疾病的潜在疗法。