Epigenetic correction of defective plasticity in a tauopathy mouse model with an acetyltransferase activator [ChIP-Seq]. Mus musculus

In the adult brain, histone acetylation is associated with activity-regulated transcriptional changes that are required for synaptic plasticity and memory. These processes are dismantled in neurodegenerative diseases. Here, we demonstrate that synaptic plasticity and memory deficiencies can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small molecule activator of CBP/p300 histone acetyltransferases (HAT). CSP-TTK21 normalized the H2B acetylation levels in many genes, including a series of super-enhancer –regulated genes, associated with plasticity and neuronal function in resting tauopathic mice. CSP-TTK21 re-established part of the learning-induced hippocampal transcriptome, including the induction of immediate early genes and memory-related genes, and the down-regulation of neuronal identity genes that bear super-enhancers. This study is the first to provide in vivo proof-of-concept evidence that direct activation of CBP/p300 HAT efficiently and selectively reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated to Alzheimer’s disease lesions in mice. Overall design: Examination of H2Bac and H3k27ac in the dorsal hippocampus by deep sequencing

在成年大脑中，组蛋白乙酰化（histone acetylation）与活性依赖的转录变化密切相关，而此类变化是突触可塑性（synaptic plasticity）与记忆形成所必需的过程。上述过程在神经退行性疾病中会遭到破坏。本研究证实，经CBP/p300组蛋白乙酰转移酶（HAT）的小分子激活剂CSP-TTK21处理后，tau蛋白病（tauopathy）小鼠模型的突触可塑性与记忆缺陷可得到恢复。CSP-TTK21可使静息态tau蛋白病小鼠中众多与可塑性及神经元功能相关的基因的H2B乙酰化水平恢复正常，其中包括一系列受超级增强子（super-enhancer）调控的基因。CSP-TTK21还可重建部分学习诱导的海马转录组（hippocampal transcriptome），包括即刻早期基因（immediate early genes）与记忆相关基因的诱导表达，以及携带超级增强子的神经元身份基因的下调。本研究首次提供了体内概念验证证据，表明直接激活CBP/p300组蛋白乙酰转移酶可高效且选择性地逆转与小鼠阿尔茨海默病（Alzheimer’s disease）病灶相关的表观遗传、转录、突触可塑性及行为缺陷。总体实验设计：通过深度测序（deep sequencing）检测背侧海马体中的H2B乙酰化与H3K27乙酰化水平。