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m6A facilitates hippocampus-dependent learning and memory through YTHDF1

Author

Listed:
  • Hailing Shi

    (The University of Chicago
    The University of Chicago
    The University of Chicago
    The University of Chicago)

  • Xuliang Zhang

    (ShanghaiTech University
    Zhejiang University)

  • Yi-Lan Weng

    (University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Zongyang Lu

    (ShanghaiTech University)

  • Yajing Liu

    (ShanghaiTech University)

  • Zhike Lu

    (The University of Chicago
    The University of Chicago
    The University of Chicago
    The University of Chicago)

  • Jianan Li

    (ShanghaiTech University)

  • Piliang Hao

    (ShanghaiTech University)

  • Yu Zhang

    (ShanghaiTech University)

  • Feng Zhang

    (University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • You Wu

    (Tongji University)

  • Jary Y. Delgado

    (The University of Chicago)

  • Yijing Su

    (University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Meera J. Patel

    (The University of Chicago)

  • Xiaohua Cao

    (Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University)

  • Bin Shen

    (Nanjing Medical University)

  • Xingxu Huang

    (ShanghaiTech University)

  • Guo-li Ming

    (University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania
    University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Xiaoxi Zhuang

    (The University of Chicago)

  • Hongjun Song

    (University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Chuan He

    (The University of Chicago
    The University of Chicago
    The University of Chicago
    The University of Chicago)

  • Tao Zhou

    (ShanghaiTech University)

Abstract

N6-methyladenosine (m6A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m6A-specific binding proteins1–5. In the nervous system, m6A is abundant and modulates various neural functions6–11. Whereas m6A marks groups of mRNAs for coordinated degradation in various physiological processes12–15, the relevance of m6A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m6A promotes protein translation of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 show learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Re-expression of YTHDF1 in the hippocampus of adult Ythdf1-knockout mice rescues the behavioural and synaptic defects, whereas hippocampus-specific acute knockdown of Ythdf1 or Mettl3, which encodes the catalytic component of the m6A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1-binding sites and m6A sites on hippocampal mRNAs identified key neuronal genes. Nascent protein labelling and tether reporter assays in hippocampal neurons showed that YTHDF1 enhances protein synthesis in a neuronal-stimulus-dependent manner. In summary, YTHDF1 facilitates translation of m6A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory.

Suggested Citation

  • Hailing Shi & Xuliang Zhang & Yi-Lan Weng & Zongyang Lu & Yajing Liu & Zhike Lu & Jianan Li & Piliang Hao & Yu Zhang & Feng Zhang & You Wu & Jary Y. Delgado & Yijing Su & Meera J. Patel & Xiaohua Cao , 2018. "m6A facilitates hippocampus-dependent learning and memory through YTHDF1," Nature, Nature, vol. 563(7730), pages 249-253, November.
  • Handle: RePEc:nat:nature:v:563:y:2018:i:7730:d:10.1038_s41586-018-0666-1
    DOI: 10.1038/s41586-018-0666-1
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    Citations

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    Cited by:

    1. Xiangyu Wang & Yan Ding & Ran Li & Rujun Zhang & Xuejun Ge & Ruifang Gao & Miao Wang & Yubing Huang & Fang Zhang & Bin Zhao & Wang Liao & Jie Du, 2023. "N6-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Fang Guo & Jun Fan & Jin-Ming Liu & Peng-Li Kong & Jing Ren & Jia-Wen Mo & Cheng-Lin Lu & Qiu-Ling Zhong & Liang-Yu Chen & Hao-Tian Jiang & Canyuan Zhang & You-Lu Wen & Ting-Ting Gu & Shu-Ji Li & Ying, 2024. "Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Wanzun Lin & Li Chen & Haojiong Zhang & Xianxin Qiu & Qingting Huang & Fangzhu Wan & Ziyu Le & Shikai Geng & Anlan Zhang & Sufang Qiu & Long Chen & Lin Kong & Jiade J. Lu, 2023. "Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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