m6A facilitates hippocampus-dependent learning and memory through YTHDF1
Open accessAbstract
N 6-methyladenosine (m 6 A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m 6 A-specific binding proteins 1-5. In the nervous system, m 6 A is abundant and modulates various neural functions 6-11. Whereas m 6 A marks groups of mRNAs for coordinated degradation in various physiological processes 12-15, the relevance of m 6 A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m 6 A 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 m 6 A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1-binding sites and m 6 A 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 m 6 A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory.
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Absence of YTHDF1 affects synaptic transmission and long-term enhancement in the hippocampus, leading to deficiencies in learning and memory.
“whereas its absence affects synaptic transmission and long-term enhancement in the hippocampus, leading to deficiencies in learning and memory.367”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [367]
YTHDF1 enhances learning and memory of neuronal stimuli by accelerating the translation of specific transcripts in the adult mouse hippocampus.
“By accelerating the translation of specific transcripts in the adult mouse hippocampus, YTHDF1 enhances learning and memory of neuronal stimuli, whereas its absence affects synaptic transmission and long-term enhancement in the hippocampus, leading to deficiencies in learning and memory.367”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [367]
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“By accelerating the translation of specific transcripts in the adult mouse hippocampus, YTHDF1 enhances learning and memory of neuronal stimuli, whereas its absence affects synaptic transmission and long-term enhancement in the hippocampus, leading to deficiencies in learning and memory.(367)”
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- Authors
- Shi, H., Zhang, X., Weng, Y.-L., Lu, Z., Liu, Y., Lu, Z., Li, J., Hao, P., Zhang, Y., Zhang, F., Wu, Y., Delgado, J. Y., Su, Y., Patel, M. J., Cao, X., Shen, B., Huang, X., Ming, G.-L., Zhuang, X., Song, H., He, C., & Zhou, T.
- Affiliations
- Howard Hughes Medical Institute (US)
- ShanghaiTech University (CN)
- University of Pennsylvania (US)
- Tongji University (CN)
- University of Chicago (US)
- East China Normal University (CN)
- State Key Laboratory of Reproductive Medicine (CN)
- Corresponding author
- Song, Hongjun
- He, Chuan
- Zhou, Tao
- ORCID
- Venue
- Nature
- Published
- 2018-10-31
- Volume
- 563
- Issue
- 7730
- Pages
- 249-253
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6226095
- OpenAlex
- W2899339826
- Cited by
- 546
- References
- 46
- Citations by year
- 2026: 51 · 2025: 71 · 2024: 67 · 2023: 79 · 2022: 79 · 2021: 98 · 2020: 64 · 2019: 36 · 2018: 1
- FWCI
- 18.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Foundation for the National Institutes of Health
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Simons Foundation Autism Research Initiative
- National Natural Science Foundation of China
- National Key Research and Development Program of China
- National Institute of Mental Health (R01MH105128)
- National Institute on Drug Abuse (R01DA043361, T32DA043469)
- National Human Genome Research Institute (RM1HG008935)
- National Institute of General Medical Sciences (R01GM113194)
- National Institute of Neurological Disorders and Stroke (R01NS047344, R21NS103159, P01NS097206, R35NS097370, R37NS047344, R56NS047344)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- N6-methyladenosine, m6A RNA methylation, YTHDF1, mRNA translation, hippocampus, learning and memory, long-term potentiation, synaptic transmission, METTL3, neurostimulation, protein synthesis, hippocampal neurons
- MeSH terms
- Adenine, Animals, Binding Sites, Female, Hippocampus, Male, Memory, Methyltransferases, Synaptic Transmission, Neuronal Plasticity, Neurons, RNA, Messenger, Protein Biosynthesis, RNA-Binding Proteins, Mice, Knockout, Mice, Spatial Learning
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