m6A facilitates hippocampus-dependent learning and memory through YTHDF1

Research output: Contribution to journalArticle

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, Bin Shen, Xingxu Huang, Guo li Ming, Xiaoxi Zhuang, Hongjun Song & 2 others Chuan He, Tao Zhou

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.

Original languageEnglish (US)
Pages (from-to)249-253
Number of pages5
JournalNature
Volume563
Issue number7730
DOIs
StatePublished - Nov 8 2018

PMID: 30401835

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m6A facilitates hippocampus-dependent learning and memory through YTHDF1. / Shi, Hailing; Zhang, Xuliang; Weng, Yi-Lan; Lu, Zongyang; Liu, Yajing; Lu, Zhike; Li, Jianan; Hao, Piliang; Zhang, Yu; Zhang, Feng; Wu, You; Delgado, Jary Y.; Su, Yijing; Patel, Meera J.; Cao, Xiaohua; Shen, Bin; Huang, Xingxu; Ming, Guo li; Zhuang, Xiaoxi; Song, Hongjun; He, Chuan; Zhou, Tao.

In: Nature, Vol. 563, No. 7730, 08.11.2018, p. 249-253.

Research output: Contribution to journalArticle

Harvard

Shi, H, Zhang, X, Weng, Y-L, 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 2018, 'm6A facilitates hippocampus-dependent learning and memory through YTHDF1' Nature, vol. 563, no. 7730, pp. 249-253. https://doi.org/10.1038/s41586-018-0666-1

APA

Shi, H., Zhang, X., Weng, Y-L., Lu, Z., Liu, Y., Lu, Z., ... Zhou, T. (2018). m6A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature, 563(7730), 249-253. https://doi.org/10.1038/s41586-018-0666-1

Vancouver

Shi H, Zhang X, Weng Y-L, Lu Z, Liu Y, Lu Z et al. m6A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature. 2018 Nov 8;563(7730):249-253. https://doi.org/10.1038/s41586-018-0666-1

Author

Shi, Hailing ; Zhang, Xuliang ; Weng, Yi-Lan ; Lu, Zongyang ; Liu, Yajing ; Lu, Zhike ; Li, Jianan ; Hao, Piliang ; Zhang, Yu ; Zhang, Feng ; Wu, You ; Delgado, Jary Y. ; Su, Yijing ; Patel, Meera J. ; Cao, Xiaohua ; Shen, Bin ; Huang, Xingxu ; Ming, Guo li ; Zhuang, Xiaoxi ; Song, Hongjun ; He, Chuan ; Zhou, Tao. / m6A facilitates hippocampus-dependent learning and memory through YTHDF1. In: Nature. 2018 ; Vol. 563, No. 7730. pp. 249-253.

BibTeX

@article{27ff2454449343a59f32395ffae12eba,
title = "m6A facilitates hippocampus-dependent learning and memory through YTHDF1",
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.",
author = "Hailing Shi and Xuliang Zhang and Yi-Lan Weng and Zongyang Lu and Yajing Liu and Zhike Lu and Jianan Li and Piliang Hao and Yu Zhang and Feng Zhang and You Wu and Delgado, {Jary Y.} and Yijing Su and Patel, {Meera J.} and Xiaohua Cao and Bin Shen and Xingxu Huang and Ming, {Guo li} and Xiaoxi Zhuang and Hongjun Song and Chuan He and Tao Zhou",
year = "2018",
month = "11",
day = "8",
doi = "10.1038/s41586-018-0666-1",
language = "English (US)",
volume = "563",
pages = "249--253",
journal = "Nature",
issn = "0028-0836",
number = "7730",

}

RIS

TY - JOUR

T1 - m6A facilitates hippocampus-dependent learning and memory through YTHDF1

AU - Shi, Hailing

AU - Zhang, Xuliang

AU - Weng, Yi-Lan

AU - Lu, Zongyang

AU - Liu, Yajing

AU - Lu, Zhike

AU - Li, Jianan

AU - Hao, Piliang

AU - Zhang, Yu

AU - Zhang, Feng

AU - Wu, You

AU - Delgado, Jary Y.

AU - Su, Yijing

AU - Patel, Meera J.

AU - Cao, Xiaohua

AU - Shen, Bin

AU - Huang, Xingxu

AU - Ming, Guo li

AU - Zhuang, Xiaoxi

AU - Song, Hongjun

AU - He, Chuan

AU - Zhou, Tao

PY - 2018/11/8

Y1 - 2018/11/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85056115397&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056115397&partnerID=8YFLogxK

U2 - 10.1038/s41586-018-0666-1

DO - 10.1038/s41586-018-0666-1

M3 - Article

VL - 563

SP - 249

EP - 253

JO - Nature

T2 - Nature

JF - Nature

SN - 0028-0836

IS - 7730

ER -

ID: 42529164