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Synaptic m6A Epitranscriptome Reveals Functional Partitioning of Localized Transcripts for Dynamic Tripartite Synapse Modulation

Daria Merkurjev, Wan-Ting Hong, Kei lida, Belinda J Goldie, Hitoshi Yamaguti, Ikumi Oomoto, Takayuki Ohara, Shin-ya Kawaguchi, Tomoo Hirano, Kelsey C Martin, Matteo Pellegrini, Dan Ohtan Wang
doi: https://doi.org/10.1101/221374
Daria Merkurjev
2Statistics Department, University of California at Los Angeles, 8125 Math Sciences Bldg. Box 951554. Los Angeles, CA 90095-1554
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Wan-Ting Hong
3Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 606-8501, Japan
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Kei lida
4Medical Research Support Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
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Belinda J Goldie
3Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 606-8501, Japan
5Society for the Promotion of Science (JSPS), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, JAPAN
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Hitoshi Yamaguti
3Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 606-8501, Japan
6Undergraduate School of Informatics and Mathematical Science, Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto 606-8501 JAPAN
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Ikumi Oomoto
3Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 606-8501, Japan
7Graduate School of Biostudies, Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 6068501, Japan
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Takayuki Ohara
3Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 606-8501, Japan
7Graduate School of Biostudies, Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 6068501, Japan
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Shin-ya Kawaguchi
8Society-Academia Collaboration for Innovation, Kyoto University, Yoshida-Honmachi, Sakuo-ku, Kyoto, 6068501, Japan
9Graduate School of Science, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto, 6068502, Japan
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Tomoo Hirano
9Graduate School of Science, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto, 6068502, Japan
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Kelsey C Martin
10Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA90095, USA
11Department of Biological Chemistry, University of California at Los Angeles, Los Angeles, CA90095, USA
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Matteo Pellegrini
12Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, CA90095, USA
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Dan Ohtan Wang
3Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 606-8501, Japan
13The Keihanshin Consortium for Fostering the Next Generation of Global Leaders in Research (K-CONNEX), Yoshida-Honmachi, Sakyo-ku, Kyotoshi, Kyoto, 606-8501, Japan
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  • For correspondence: dwang@icems.kyoto-u.ac.jp
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Abstract

A localized transcriptome at the synapse facilitates synapse-, stimulus-, and transcript-specific synthesis of the local proteome in response to neuronal activity. While enzyme-mediated mRNA modifications have been shown to regulate cellular mRNA turnover and translation, the role of these modifications in regulating synaptic RNA has not been studied. We established low-input m6A-seq of synaptosomal RNA to determine the chemically modified local transcriptome in healthy adult mouse forebrain and identified 4,329 selectively enriched m6A RNA peaks in 2,987 genes, which we refer to as the synaptic m6A epitranscriptome (SME). SME is functionally enriched in synthesis and modulation of tripartite synapses, and in pathways implicated in neurodevelopmental and neuropsychiatric diseases. Interrupting m6A-mediated regulation via knockdown of reader YTHDF1 in hippocampal neurons alters expression of SME member Apc, and causes synaptic malfunctions manifesting immature spine morphology and dampened excitatory synaptic transmission concomitant with decreased PSD-95 clustering and GluA1 surface expression. Our findings indicate that chemical modifications of synaptic mRNAs critically contribute to synaptic function.

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Posted November 17, 2017.
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Synaptic m6A Epitranscriptome Reveals Functional Partitioning of Localized Transcripts for Dynamic Tripartite Synapse Modulation
Daria Merkurjev, Wan-Ting Hong, Kei lida, Belinda J Goldie, Hitoshi Yamaguti, Ikumi Oomoto, Takayuki Ohara, Shin-ya Kawaguchi, Tomoo Hirano, Kelsey C Martin, Matteo Pellegrini, Dan Ohtan Wang
bioRxiv 221374; doi: https://doi.org/10.1101/221374
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Synaptic m6A Epitranscriptome Reveals Functional Partitioning of Localized Transcripts for Dynamic Tripartite Synapse Modulation
Daria Merkurjev, Wan-Ting Hong, Kei lida, Belinda J Goldie, Hitoshi Yamaguti, Ikumi Oomoto, Takayuki Ohara, Shin-ya Kawaguchi, Tomoo Hirano, Kelsey C Martin, Matteo Pellegrini, Dan Ohtan Wang
bioRxiv 221374; doi: https://doi.org/10.1101/221374

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