m(6)A facilitates hippocampus-dependent learning and memory through YTHDF1.
m(6)A facilitates hippocampus-dependent learning and memory through YTHDF1.
复制标题
DOI：
10.1038/s41586-018-0666-1
复制
发表时间：
2018-11
期刊：
影响因子：
64.8
通讯作者：
Zhou T
中科院分区：
文献类型：
--
作者：
Shi H;Zhang X;Weng YL;Lu Z;Liu Y;Lu Z;Li J;Hao P;Zhang Y;Zhang F;Wu Y;Delgado JY;Su Y;Patel MJ;Cao X;Shen B;Huang X;Ming GL;Zhuang X;Song H;He C;Zhou T
n6 -甲基腺苷（N6-methyladenosine, m6A）是哺乳动物信使RNA （mrna）上最常见的内部RNA修饰，通过m6A特异性结合蛋白调节修饰转录本的命运和功能。m6A在神经系统中含量丰富，调节多种神经功能。虽然m6A标记了在各种生理过程中协调降解的mRNA组，但在体内，m6A在mRNA翻译中的相关性仍然很大程度上未知。本研究表明，m6A通过其结合蛋白Ythdf1促进成年小鼠海马响应神经元刺激的靶转录物的蛋白质合成，从而促进学习和记忆。基因缺失Ythdf1 （Ythdf1- ko）的小鼠表现出学习和记忆缺陷，以及海马突触传递和长时程增强受损。成年Ythdf1- ko小鼠海马中Ythdf1的重新表达可以挽救行为和突触缺陷，而海马特异性的Ythdf1或m6A甲基转移酶复合物的催化成分Mettl3的急性敲低则再现了海马缺陷。海马mrna上Ythdf1结合位点和m6A位点的转录组全图谱揭示了关键的神经元基因。海马神经元新生蛋白标记和tether报告细胞实验显示，Ythdf1以神经元刺激依赖的方式增强蛋白质合成。总的来说，我们的研究结果揭示了学习和记忆中mRNA m6A甲基化的途径，该途径是通过Ythdf1介导的，以响应刺激。
N6-methyladenosine (m6A), the most prevalent internal RNA modification on mammalian messenger RNAs (mRNAs), regulates fates and functions of modified transcripts through m6A-specific binding proteins. m6A is abundant in the nervous system and modulates various neural functions. While m6A marks groups of mRNAs for coordinated degradation in various physiological processes, the relevance of m6A in mRNA translation remains largely unknown in vivo. Here we show that, through its binding protein Ythdf1, m6A promotes protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 (Ythdf1-KO) exhibit learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Ythdf1 re-expression in the hippocampus of adult Ythdf1-KO mice rescues behavioral and synaptic defects, while hippocampus-specific acute knockdown of Ythdf1 or Mettl3, the catalytic component of m6A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of Ythdf1 binding sites and m6A sites on hippocampal mRNAs uncovered key neuronal genes. Nascent protein labeling and tether reporter assays in hippocampal neurons revealed that Ythdf1 enhances protein synthesis in a neuronal-stimulus-dependent manner. Collectively, our results uncover a pathway of mRNA m6A methylation in learning and memory, which is mediated through Ythdf1 in response to stimuli.
登录
查看更多内容
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
64.8
作者：
Lence, Tina;Akhtar, Junaid;Roignant, Jean-Yves
通讯作者：
Roignant, Jean-Yves
影响因子：
64.5
作者：
Meyer KD;Saletore Y;Zumbo P;Elemento O;Mason CE;Jaffrey SR
通讯作者：
Jaffrey SR
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
64.5
作者：
Guo JU;Su Y;Zhong C;Ming GL;Song H
通讯作者：
Song H