Neuron ( IF 14.7 ) Pub Date : 2021-01-26 , DOI: 10.1016/j.neuron.2021.01.005
Xiaohui Li , Juan Zhang , Dingfeng Li , Cheng He , Keqiang He , Tian Xue , Lili Wan , Chi Zhang , Qiang Liu
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Astrocytes metabolically interact with neighboring neurons by providing multiple substances to neurons. How astrocytes regulate neural functions via altering the neuronal metabolic state remains elusive. Here, we demonstrate that astrocytic ApoE vectors a variety of microRNAs (miRNAs), and these miRNAs specifically silence genes involved in neuronal cholesterol biosynthesis, ultimately accounting for accumulation of the pathway-initiating substrate acetyl-CoA. Consequently, histone acetylation is promoted, and transcription is activated in neurons. Functionally, we demonstrate that ApoE-mediated neuronal histone acetylation leads to increased H3K27ac enrichment in the promoters of multiple neuronal immediate early genes and subsequently to enhanced memory consolidation in mice. Importantly, human ApoE4 vectors lower levels of miRNAs than ApoE3 and therefore is less capable of metabolic and epigenetic regulation in neurons. Collectively, our findings define an astrocytic ApoE-mediated neuronal epigenetic mechanism as a novel means through which astrocytes modulate brain connectivity and function.
中文翻译:
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星形细胞ApoE重新编程神经元胆固醇代谢和组蛋白乙酰化介导的记忆
通过向神经元提供多种物质,星形胶质细胞与邻近的神经元发生代谢相互作用。星形胶质细胞如何通过改变神经元代谢状态来调节神经功能仍然难以捉摸。在这里,我们证明了星形细胞ApoE载体多种microRNA(miRNA),并且这些miRNA特异性沉默了涉及神经元胆固醇生物合成的基因,最终导致了途径起始底物乙酰辅酶A的积累。因此,促进了组蛋白乙酰化,并在神经元中激活了转录。在功能上,我们证明ApoE介导的神经元组蛋白乙酰化导致多个神经元立即早期基因启动子中的H3K27ac富集增加,并随后增强了小鼠的记忆整合。重要的,人ApoE4载体的miRNA水平低于ApoE3,因此在神经元中代谢和表观遗传调控的能力较弱。总的来说,我们的发现将星形胶质细胞介导的ApoE介导的神经元表观遗传机制定义为一种新的途径,通过这种途径星形胶质细胞可以调节大脑的连通性和功能。