Li Xiaohui, Zhang Juan, Li Dingfeng, He Cheng, He Keqiang, Xue Tian, Wan Lili, Zhang Chi, Liu Qiang
Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei 230026, China.
Neuron. 2021 Mar 17;109(6):957-970.e8. doi: 10.1016/j.neuron.2021.01.005. Epub 2021 Jan 26.
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.
星形胶质细胞通过向神经元提供多种物质与邻近神经元进行代谢相互作用。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不清楚。在这里，我们证明星形胶质细胞载脂蛋白E（ApoE）携带多种微小RNA（miRNA），这些miRNA特异性沉默参与神经元胆固醇生物合成的基因，最终导致该途径起始底物乙酰辅酶A的积累。因此，组蛋白乙酰化得到促进，神经元中的转录被激活。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即刻早期基因启动子中H3K27ac富集增加，进而增强小鼠的记忆巩固。重要的是，人类ApoE4携带的miRNA水平低于ApoE3，因此在神经元中进行代谢和表观遗传调控的能力较弱。总之，我们的研究结果定义了一种星形胶质细胞ApoE介导的神经元表观遗传机制，作为星形胶质细胞调节大脑连接性和功能的一种新方式。
