Leung How-Wing, Foo Gabriel, VanDongen Antonius
Duke-NUS Medical School, Singapore 169857, Singapore.
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Biomedicines. 2022 Aug 11;10(8):1946. doi: 10.3390/biomedicines10081946.
The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal neurons. Both these histone modifications, H3K27Ac and H3K9Ac, have recently been shown to be upregulated in late-onset Alzheimer's disease (AD). When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes, which included genes associated with synaptic function, neuronal plasticity, intrinsic excitability, and signalling pathways. Interestingly, about 100 Arc-dependent genes are associated with the pathophysiology of AD. When endogenous Arc expression was induced in HEK293T cells, the transcription of many neuronal genes was increased, suggesting that Arc can control expression in the absence of activated signalling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and suggest that it plays a significant role in the pathophysiology of AD.
即刻早期基因Arc是突触功能的主要调节因子，也是记忆巩固的关键决定因素。在此，我们表明Arc与动态染色质相互作用，并与培养的大鼠海马神经元中活性增强子和转录的组蛋白标记密切相关。最近发现，这两种组蛋白修饰，即H3K27Ac和H3K9Ac，在晚发性阿尔茨海默病（AD）中上调。当使用短发夹RNA阻止药理学网络激活诱导Arc时，超过1900个基因的表达谱发生改变，这些基因包括与突触功能、神经元可塑性、内在兴奋性和信号通路相关的基因。有趣的是，约100个Arc依赖性基因与AD的病理生理学相关。当在HEK293T细胞中诱导内源性Arc表达时，许多神经元基因的转录增加，这表明Arc在没有激活的信号通路的情况下也能控制基因表达。综上所述，这些数据确立了Arc作为神经元活动依赖性基因表达的主要调节因子，并表明它在AD的病理生理学中起重要作用。
